Microglia and Alzheimer

1. Asanuma M, Miyazaki I, Tsuji T, Ogawa N (2003) [New aspects of neuroprotective effects of nonsteroidal anti-inflammatory drugs]. Nihon Shinkei Seishin Yakurigaku Zasshi 23:111-119
   Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory, analgesic and antipyretic activities and are involved in the suppression of prostaglandin synthesis by inhibiting cyclooxygenase (COX), a prostaglandin synthesizing enzyme. It has been recently revealed that NSAIDs also possess inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors and nuclear receptors which are related to inflammatory reactions. Since it has been reported that inflammatory processes are associated with the pathophysiology of several neurodegenerative diseases and that NSAIDs inhibit amyloid beta-protein-induced neurotoxicity to reduce the risk for Alzheimer's disease, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs. It has been clarified that the drugs exert neuroprotective effects, which are not related to their COX-inhibiting property, on pathophysiology of various neurological disorders. In this article, new aspects of neuroprotective effects of NSAIDs have been reviewed, especially, in Alzheimer's disease and Parkinson's disease, discussing various pharmacological effects of NSAIDs other than their inhibitory action on COX

2. Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T (2003) Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc.Natl.Acad.Sci.U.S.A 100:2023-2028
   Abstract: Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing beta-amyloid peptide (Abeta) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Abeta peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against Abeta. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different Abeta epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of Abeta were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble Abeta was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on Microglial cells seemed more important than high affinity for Abeta itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease

3. Blasko I, Grubeck-Loebenstein B (2003) Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease. Drugs Aging 20:101-113
   Abstract: The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by Microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered

4. Chaney MO, Baudry J, Esh C, Childress J, Luehrs DC, Kokjohn TA, Roher AE (2003) A beta, aging, and Alzheimer's disease: a tale, models, and hypotheses. Neurol.Res. 25:581-589
   Abstract: In this paper we explore the potential functional role of the A beta peptides in the context of Alzheimer's disease (AD). We begin by defining the morphology of the amyloid deposits in relation to surrounding glial cells and, more importantly, in relation to the brain vasculature. Amyloid accumulation in the brain's microvasculature causes disturbances in the blood-brain barrier (BBB), and in larger arteries, impairment in control of regional cerebral blood flow due to myocyte degeneration. We postulate that the deposition of vascular amyloid may represent a hydrophobic protein plaster to seal leaks in the BBB, occasionally observed in aging and catastrophically common in AD. The vasoconstrictive activity of A beta may also be related to leaky vessels whereby decreasing the arterial diameter may also help to control breaches in the BBB. The admission of plasma neurotoxic proteins into the brain may be controlled by activation of Microglia elicited by soluble A beta peptides creating a subtle, but permanent brain inflammatory reaction. We also delve into the influence that cholesterol metabolism may have in membrane topology and A beta production, and the close correlations that exist between cardiovascular disease and AD. Finally, we speculate about the possibility of a peripheral source of A beta that may, by crossing the BBB, contribute to the vascular and parenchymal deposits of A beta in the AD brain

5. Chaudhury AR, Gerecke KM, Wyss JM, Morgan DG, Gordon MN, Carroll SL (2003) Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease. J.Neuropathol.Exp.Neurol. 62:42-54
   Abstract: Neuregulin-1 (NRG-1) regulates developmental neuronal survival and synaptogenesis, astrocytic differentiation, and Microglial activation. Given these NRG-1 actions, we hypothesized that the synaptic loss, gliosis, inflammation, and neuronal death occurring in Alzheimer disease (AD) is associated with altered expression of NRG-1 and its receptors (the erbB2, erbB3, and erbB4 membrane tyrosine kinases). We examined the expression and distribution of NRG-1 and the erbB kinases in the hippocampus of AD patients and cognitively normal controls and in transgenic mice that coexpress AD-associated mutations of the beta amyloid precursor protein (APP(K670N,M671L)) and presenilin-1 (PS1(M146L)). In the hippocampi of both control humans and wild type mice, NRG-1 and the 3 erbB receptors are expressed in distinct cellular compartments of hippocampal neurons. All 4 molecules are associated with neuronal cell bodies, but only NRG-1, erbB2, and erbB4 are present in synapse-rich regions. In AD and in the doubly transgenic mouse, erbB4 is expressed by reactive astrocytes and Microglia surrounding neuritic plaques. In AD brains, Microglia and, to a lesser extent, dystrophic neurites, also upregulate NRG-1 in neuritic plaques, suggesting that autocrine and/or paracrine interactions regulate NRG-1 action within these lesions. NRG-1 and erbB4, as well as erbB2, are similarly associated with neuritic plaques in the doubly transgenic mice. Thus, in AD the hippocampal distribution of NRG-1 and erbB4 is altered. The similarities between the alterations in the expression of NRG-1 and its receptors in human AD and in APP(K670N;M671L)/PS1(M146L) mutant mice suggests that this animal model may be very informative in deciphering the potential role of these molecules in AD

6. Chauhan NB, Siegel GJ (2003) Intracerebroventricular passive immunization with anti-Abeta antibody in Tg2576. J.Neurosci.Res. 74:142-147
   Abstract: Current Alzheimer's disease (AD) research has established the fact that excessive genesis of Abeta derived from amyloidogenic processing of beta-amyloid (Abeta) precursor protein is fundamental to AD pathogenesis. There has been considerable interest in using immunization strategies for clearing excessive Abeta. Studies in animal models of AD have shown that active immunizations or systemic passive immunizations reduced cerebral plaque load and improved behavioral deficits. However, clinical translation of an active immunization strategy was interrupted because of evidence for meningoencephalitis produced in some patients who received Abeta vaccine. Studies in animal models have shown perimicrovascular hemorrhages and inflammation after sustained systemic immunizations in animals with vascular amyloid. In this light, our data showing the effects of a single intracerebroventricular (ICV) injection of anti-Abeta in the Alzheimer's Swedish mutant model Tg2576 are intriguing. We have previously demonstrated that a single ICV injection of anti-Abeta into the third ventricle of 10-month-old Tg2576 mice reduced cerebral plaques, reversed Abeta-induced depletion of presynaptic SNAP-25, and abolished astroglial activation as seen 1 month post-injection (Chauhan and Siegel [2002] J. Neurosci. Res. 69:10-23). The present report demonstrates that a single ICV injection of 10 microg anti-Abeta in 10-month-old Tg2576 mice reduced cerebral plaques, with decreased inflammation at this stage as evidenced by a reduced number of interleukin-1beta-positive Microglia surrounding Congophilic plaques. Moreover, at this particular age, no microhemorrhage was discernible, as evidenced by the absence of hemosiderin deposition after a single ICV injection of anti-Abeta. This is the first report demonstrating absence of microhemorrhage and reduced inflammation after the ICV introduction of anti-Abeta in Tg2576 mice at 10 months of age. These facts indicate that, although invasive, ICV injection of anti-Abeta may be a safer method of vaccination in AD, possibly through reducing the vascular exposure to antibody. Further studies are warranted to determine the lasting effects of a single ICV anti-Abeta injection in animals with and without abundant plaque burden and at older ages

7. Check E (2003) Battle of the mind. Nature 422:370-372

8. Czapiga M, Colton CA (2003) Microglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport. J.Neuroimmunol. 134:44-51
   Abstract: The APOE4 genotype is a known risk factor for Alzheimer's disease (AD) and is associated with poorer outcomes after neuropathological insults. To understand APOE's function, we have examined Microglia, the CNS specific macrophage, in transgenic mice expressing the human APOE3 and APOE4 gene allele. Our data demonstrate that arginine uptake is enhanced in APOE4 Microglia compared to APOE3 Microglia. The increased arginine uptake in APOE4 Tg Microglia is associated with an increased expression of mRNA for cationic amino acid transporter-1 (Cat1), a constuitively expressed member of the arginine selective transport system (the y+ transport system) found in most cells. The macrophage-associated transporter, cationic amino acid transporter 2B (Cat2B) did not demonstrate a change in mRNA expression. This change in Microglial arginine transport suggests a potential impact of the APOE4 gene allele on those biochemical pathways such as NO production or cell proliferation to which arginine contributes

9. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE (2003) Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J.Neurosci. 23:8532-8538
   Abstract: Direct immunization with amyloid beta protein (Abeta) and passive transfer of anti-Abeta antibodies reduce Abeta accumulation and attenuate cognitive deficits in transgenic models of Alzheimer's disease (AD). The reduction in Abeta deposition has been proposed to involve Microglial phagocytosis of Abeta immune complexes via Fc receptors (FcRs). We have examined the efficacy of Abeta immunization in amyloid precursor protein (APP) transgenic mice crossed into FcR-gamma chain knock-out mice (FcRgamma-/-). As might be expected from previous studies on macrophages, phagocytosis of Abeta immune complexes via FcR was completely impaired in Microglia cells isolated from FcRgamma-/- mice. Thus, we immunized APP Tg2576 transgenic mice that were crossed in the FcRgamma-/- background with Abeta1-42 and then analyzed the effect on Abeta accumulation. In APP Tg2576 transgenic mice crossed to FcRgamma-/-, Abeta1-42 immunization significantly attenuated Abeta deposition, as assessed by both biochemical and immunohistological methods. The reduction in Abeta accumulation was equivalent to the reduction in deposition seen in Abeta1-42 immunized, age-matched, FcR-sufficient Tg2576 mice. We conclude that after Abeta immunization, the effects of anti-Abeta antibodies on Abeta deposition in APP Tg2576 transgenic mice are not dependent on FcR-mediated phagocytic events

10. Dodel RC, Hampel H, Du Y (2003) Immunotherapy for Alzheimer's disease. Lancet Neurol. 2:215-220
    Abstract: Recent studies in murine models of Alzheimer's disease (AD) have found that active immunisation with amyloid-beta peptide (Abeta) or passive immunisation with Abeta antibodies can lessen the severity of Abeta-induced neuritic plaque pathology through the activation of Microglia. These antibodies can be detected in the serum and CSF. Whether they slow down or speed up the development and progression of AD has not been determined. Furthermore, the conditions that induce formation of such antibodies are unknown, or how specific they are to AD. However, the evidence suggests at least a potential beneficial role for some features of neuroinflammation in AD. A clinical phase II study of an active immunisation approach with AN1792 was started in 2001, but was recently suspended after some patients developed serious adverse events. These were most likely caused by the activation of the proinflammatory cascade. Immunotherapy approaches represent fascinating ways to test the amyloid hypothesis and may offer genuine opportunities to modify disease progression. This review focuses on immunisation strategies and details of the pathways involved in antibody clearance of Abeta

11. El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD (2003) CD36 mediates the innate host response to beta-amyloid. J.Exp.Med. 197:1657-1666
    Abstract: Accumulation of inflammatory Microglia in Alzheimer's senile plaques is a hallmark of the innate response to beta-amyloid fibrils and can initiate and propagate neurodegeneration characteristic of Alzheimer's disease (AD). The molecular mechanism whereby fibrillar beta-amyloid activates the inflammatory response has not been elucidated. CD36, a class B scavenger receptor, is expressed on Microglia in normal and AD brains and binds to beta-amyloid fibrils in vitro. We report here that Microglia and macrophages, isolated from CD36 null mice, had marked reductions in fibrillar beta-amyloid-induced secretion of cytokines, chemokines, and reactive oxygen species. Intraperitoneal and stereotaxic intracerebral injection of fibrillar beta-amyloid in CD36 null mice induced significantly less macrophage and Microglial recruitment into the peritoneum and brain, respectively, than in wild-type mice. Our data reveal that CD36, a major pattern recognition receptor, mediates Microglial and macrophage response to beta-amyloid, and imply that CD36 plays a key role in the proinflammatory events associated with AD

12. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc.Natl.Acad.Sci.U.S.A 100:4162-4167
    Abstract: Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and Microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD

13. Frampton M, Harvey RJ, Kirchner V (2003) Propentofylline for dementia. Cochrane.Database.Syst.Rev.CD002853
    Abstract: BACKGROUND: Propentofylline is a novel therapeutic agent for dementia that readily crosses the blood-brain barrier and acts by blocking the uptake of adenosine and inhibiting the enzyme phosphodiesterase. In vitro and in vivo its mechanism of action appears to be twofold; it inhibits the production of free radicals and reduces the activation of Microglial cells. It therefore interacts with the inflammatory processes that are thought to contribute to dementia, and given its mechanism of action is a possible disease modifying agent rather than a purely symptomatic treatment. OBJECTIVES: To determine the clinical efficacy and safety of propentofylline for people with dementia. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 5 February 2003. Aventis, the manufacturing pharmaceutical company, was asked for data from unpublished studies but declined to enter into correspondence. SELECTION CRITERIA: Unconfounded double-blind randomized controlled trials of propentofylline compared with a placebo or another treatment group. DATA COLLECTION AND ANALYSIS: There were detailed reports of only four of the nine included studies. The efficacy of propentofylline was reviewed for undifferentiated dementia as there were not enough data to attempt a subgroup analysis for the types of dementia. MAIN RESULTS: The following statistically significant treatment effects in favour of propentofylline are reported. Cognition at 3, 6 and 12 months including MMSE at 12 months. [MD 1.2, 95%CI 0.12 to 2.28, P=0.03] Severity of dementia at 3, 6 and 12 months including CGI at 12 months [MD -0.21, 95%CI -0.39 to -0.03, P=0.03]. Activities of Daily Living (NAB) at 6 and 12 months [MD -1.20, 95%CI -2.22 to -0.18, P=0.02]. Global Assessment (CGI) at 3 months [MD -0.48, 95% CI -0.75 to -0.21, P=0.0006], but not at later times. Tolerability There were minimal data on adverse effects and drop-outs. There were a statistically significant treatment effects in favour of placebo at 12 months, for the number of dropouts, [OR=1.43, 95%CI 1.04 to 1.90, P=0.03]. REVIEWER'S CONCLUSIONS: There is limited evidence that propentofylline might benefit cognition, global function and activities of daily living of people with Alzheimer's disease and/or vascular dementia. The meta-analyses reported here are far from satisfactory as a summary of the efficacy of propentofylline, considering the unpublished information on another 1200 patients in randomized trials that exists. Unfortunately Aventis has been unwilling to correspond with the authors, significantly limiting the scope of this review

14. Gomez-Tortosa E, Gonzalo I, Fanjul S, Sainz MJ, Cantarero S, Cemillan C, Yebenes JG, del Ser T (2003) Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease. Arch.Neurol. 60:1218-1222
    Abstract: BACKGROUND: Most patients with dementia with Lewy bodies (DLB) exhibit diffuse plaque-only pathology with rare neocortical neurofibrillary tangles (NFTs), as opposed to the widespread cortical neurofibrillary-tau involvement in Alzheimer disease (AD). Another pathological difference is the astrocytic and Microglial inflammatory responses, including release of interleukins (ILs), around the neuritic plaques and NFTs in AD brains that are absent or much lower in DLB. We analyzed cerebrospinal fluid (CSF) markers that reflect the pathological differences between AD and DLB. OBJECTIVE: To determine CSF concentrations of tau, beta-amyloid, IL-1beta, and IL-6 as potential diagnostic clues to distinguish between AD and DLB. METHODS: We measured total tau, beta-amyloid1-42, IL-1beta, and IL-6 levels in CSF samples of 33 patients with probable AD without parkinsonism, 25 patients with all the core features of DLB, and 46 age-matched controls. RESULTS: Patients with AD had significantly higher levels of tau protein than patients with DLB and controls (P<.001). The most efficient cutoff value provided 76% specificity to distinguish AD and DLB cases. Patients with AD and DLB had lower, but not significantly so, beta-amyloid levels than controls. The combination of tau and beta-amyloid levels provided the best sensitivity (84%) and specificity (79%) to differentiate AD vs controls but was worse than tau values alone in discriminating between AD and DLB. Beta-amyloid levels had the best correlation with disease progression in both AD and DLB (P =.01). There were no significant differences in IL-1beta levels among patients with AD, patients with DLB, and controls. Patients with AD and DLB showed slightly, but not significantly, higher IL-6 levels than controls. CONCLUSIONS: The tau levels in CSF may contribute to the clinical distinction between AD and DLB. Beta-amyloid CSF levels are similar in both dementia disorders and reflect disease progression better than tau levels. Interleukin CSF concentrations do not distinguish between AD and DLB

15. Hartig W, Paulke BR, Varga C, Seeger J, Harkany T, Kacza J (2003) Electron microscopic analysis of nanoparticles delivering thioflavin-T after intrahippocampal injection in mouse: implications for targeting beta-amyloid in Alzheimer's disease. Neurosci.Lett. 338:174-176
    Abstract: Prevention of beta-amyloid (Abeta) production, aggregation and formation of Abeta deposits is a key pharmacological target in Alzheimer's disease. The passage of Abeta-binding compounds through the blood-brain barrier is often hampered for free ligands, whereas it is enhanced by drug encapsulation in nanoparticles. Here, we describe the preparation and characterization of polymeric carriers containing thioflavin-T as a marker for fibrillar Abeta. This study is then focused on electron microscopic analyses of thioflavin-T after injection of thioflavin-T-containing nanoparticles into the mouse hippocampus. Therefore, the photoconversion of fluorescent thioflavin-T as model drug was performed in tissues fixed 3 days post-injection. Thioflavin-T delivered from nanospheres was predominantly found in neurons and Microglia. Our data suggest that drugs delivered by nanoparticles might target Abeta in the brain

16. Hartlage-Rubsamen M, Zeitschel U, Apelt J, Gartner U, Franke H, Stahl T, Gunther A, Schliebs R, Penkowa M, Bigl V, Rossner S (2003) Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent. Glia 41:169-179
    Abstract: The beta-site APP-cleaving enzyme (BACE1) is a prerequisite for the generation of beta-amyloid peptides, which give rise to cerebrovascular and parenchymal beta-amyloid deposits in the brain of Alzheimer's disease patients. BACE1 is neuronally expressed in the brains of humans and experimental animals such as mice and rats. In addition, we have recently shown that BACE1 protein is expressed by reactive astrocytes in close proximity to beta-amyloid plaques in the brains of aged transgenic Tg2576 mice that overexpress human amyloid precursor protein carrying the double mutation K670N-M671L. To address the question whether astrocytic BACE1 expression is an event specifically triggered by beta-amyloid plaques or whether glial cell activation by other mechanisms also induces BACE1 expression, we used six different experimental strategies to activate brain glial cells acutely or chronically. Brain sections were processed for the expression of BACE1 and glial markers by double immunofluorescence labeling and evaluated by confocal laser scanning microscopy. There was no detectable expression of BACE1 protein by activated Microglial cells of the ameboid or ramified phenotype in any of the lesion paradigms studied. In contrast, BACE1 expression by reactive astrocytes was evident in chronic but not in acute models of gliosis. Additionally, we observed BACE1-immunoreactive astrocytes in proximity to beta-amyloid plaques in the brains of aged Tg2576 mice and Alzheimer's disease patients

17. Holmes C, El Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH (2003) Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease. J.Neurol.Neurosurg.Psychiatry 74:788-789
    Abstract: Activated Microglia, the resident macrophages of the brain, are a feature of Alzheimer's disease. Animal models suggest that when activated Microglia are further activated by a subsequent systemic infection this results in significantly raised levels of interleukin 1beta within the CNS, which may in turn potentiate neurodegeneration. This prospective pilot study in Alzheimer's disease subjects showed that cognitive function can be impaired for at least two months after the resolution of a systemic infection and that cognitive impairment is preceded by raised serum levels of interleukin 1beta. These relations were not confounded by the presence of any subsequent systemic infection or by baseline cognitive scores. Further research is needed to determine whether recurrent systemic infections drive cognitive decline in Alzheimer's disease subjects through a cytokine mediated pathway

18. Jayakumar R, Kusiak JW, Chrest FJ, Demehin AA, Murali J, Wersto RP, Nagababu E, Ravi L, Rifkind JM (2003) Red cell perturbations by amyloid beta-protein. Biochim.Biophys.Acta 1622:20-28
    Abstract: Amyloid beta-protein (A beta) accumulation in brain is thought to be important in causing the neuropathology of Alzheimer's disease (AD). A beta interactions with both neurons and Microglial cells play key roles in AD. Since vascular deposition of A beta is also implicated in AD, the interaction of red cells with these toxic aggregates gains importance. However, the effects of A beta interactions with red blood cells are less well understood. Synthetic amyloid beta-protein (1-40) was labeled with biotin and preincubated at 37 degrees C for 4, 14 and 72 h to produce fibrils. Flow cytometry was used to study the binding of these fibrils to red cells. The amyloid fibrils had a high affinity for the red cell with increased binding for the larger fibrils produced by longer preincubation. Bovine serum albumin (BSA) did not reverse the binding, but actually resulted in a more efficient binding of the A beta fibrils to the red cells. The interaction of A beta with red cells increased the mean cell volume and caused the cells to become more spherical. This effect was greater for the longer fibrils. At the same time the interaction of A beta with red cells produced an increase in their fluorescence measured after 16-h incubation at 37 degrees C. This increase in fluorescence is attributed to the formation of fluorescent heme degradation products. The effect of prior hemoglobin oxidation, catalase inhibition and glutathione peroxidase inhibition indicated that the amyloid-induced oxidative damage to the red cell involved hydrogen peroxide-induced heme degradation. These results suggest that amyloid interactions with the red cell may contribute to the pathology of AD

19. Katsuse O, Iseki E, Kosaka K (2003) Immunohistochemical study of the expression of cytokines and nitric oxide synthases in brains of patients with dementia with Lewy bodies. Neuropathology. 23:9-15
    Abstract: Regional expression of cytokines (IL-1alpha, TNF-alpha), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) was immunohistochemically investigated in the brains of patients with dementia with Lewy bodies (DLB), compared with those of patients with Alzheimer's disease (AD) and non-demented elderly persons. It has been reported that inflammatory responses by cytokines and oxygen free radicals such as nitric oxide (NO) are associated with damaged neurons, degenerative neurites or amyloid deposits in AD brains. In the present study, overexpression of IL-1alpha, TNF-alpha and iNOS was demonstrated in the amygdala, hippocampus, entorhinal and insular cortices of DLB brains, which are pathologically the most vulnerable regions in DLB brains as well as AD brains. In addition, some Lewy body (LB)-bearing neurons were involved by the processes of IL-1alpha- and TNF-alpha-positive Microglia, and most extracellular LB were associated with the processes of TNF-alpha- and iNOS-positive astroglia. Glial involvement was also found around neuritic plaques and extracellular neurofibrillary tangles. In contrast, the expression of nNOS was reduced in the amygdala of DLB brains showing severe Lewy pathology. These findings suggest that cytokines and NO are significantly implicated in neuronal damage and death including LB formation in DLB brains

20. Kitamura Y, Nomura Y (2003) Stress proteins and glial functions: possible therapeutic targets for neurodegenerative disorders. Pharmacol.Ther. 97:35-53
    Abstract: Recent findings suggest that unfolded or misfolded proteins participate in the pathology of several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Usually, several stress proteins and glial cells act as intracellular molecular chaperones and show chaperoning neuronal function, respectively. In the brains of patients with neurodegenerative disorders, however, stress proteins are expressed and frequently associated with protein aggregates, and glial cells are activated around degenerative regions. In addition, several stress proteins and glial cells may also regulate neuronal cell death and loss. Therefore, some types of stress proteins and glial cells are considered to be neuroprotective targets. We summarize the current findings regarding the neuroprotective effects of stress proteins and glial cells, and discuss the possibility of using this knowledge to develop new therapeutic strategies to treat neurodegeneration

21. Lambert JC, Luedecking-Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, Iwatsubo T, Pasquier F, Frigard B, Conneally PM, Chartier-Harlin MC, DeKosky ST, Lendon C, Mann D, Kamboh MI, Amouyel P (2003) Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. J.Med.Genet. 40:424-430
    Abstract: Although possession of the epsilon 4 allele of the apolipoprotein E gene appears to be an important biological marker for Alzheimer's disease (AD) susceptibility, strong evidence indicates that at least one additional risk gene exists on chromosome 12. Here, we describe an association of the 3'-UTR +1073 C/T polymorphism of the OLR1 (oxidised LDL receptor 1) on chromosome 12 with AD in French sporadic (589 cases and 663 controls) and American familial (230 affected sibs and 143 unaffected sibs) populations. The age and sex adjusted odds ratio between the CC+CT genotypes versus the TT genotypes was 1.56 (p=0.001) in the French sample and 1.92 (p=0.02) in the American sample. Furthermore, we have discovered a new T/A polymorphism two bases upstream of the +1073 C/T polymorphism. This +1071 T/A polymorphism was not associated with the disease, although it may weakly modulate the impact of the +1073 C/T polymorphism. Using 3'-UTR sequence probes, we have observed specific DNA protein binding with nuclear proteins from lymphocyte, astrocytoma, and neuroblastoma cell lines, but not from the Microglia cell line. This binding was modified by both the +1071 T/A and +1073 C/T polymorphisms. In addition, a trend was observed between the presence or absence of the +1073 C allele and the level of astrocytic activation in the brain of AD cases. However, Abeta(40), Abeta(42), Abeta total, and Tau loads or the level of Microglial cell activation were not modulated by the 3'-UTR OLR1 polymorphisms. Finally, we assessed the impact of these polymorphisms on the level of OLR1 expression in lymphocytes from AD cases compared with controls. The OLR1 expression was significantly lower in AD cases bearing the CC and CT genotypes compared with controls with the same genotypes. In conclusion, our data suggest that genetic variation in the OLR1 gene may modify the risk of AD

22. Lesne S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buee L, Plawinski L, Delacourte A, MacKenzie ET, Buisson A, Vivien D (2003) Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice. J.Biol.Chem. 278:18408-18418
    Abstract: Accumulation of the amyloid-beta peptide (Abeta) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, has been correlated in vivo with Abeta accumulation in transgenic mice and recently with Abeta clearance by activated Microglia. Here, we demonstrate that TGF-beta1 drives the production of Abeta40/42 by astrocytes leading to Abeta production in TGF-beta1 transgenic mice. First, TGF-beta1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-beta1-responsive element in the 5'-untranslated region (+54/+74) of the APP promoter. Second, we demonstrated an increased release of soluble APP-beta which led to TGF-beta1-induced Abeta generation in both murine and human astrocytes. These results demonstrate that TGF-beta1 potentiates Abeta production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients

23. Lorenzl S, Albers DS, Relkin N, Ngyuen T, Hilgenberg SL, Chirichigno J, Cudkowicz ME, Beal MF (2003) Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease. Neurochem.Int. 43:191-196
    Abstract: Matrix metalloproteinases (MMPs) may play a role in the pathophysiology of Alzheimer's disease (AD). MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are elevated in postmortem brain tissue of AD patients. MMPs and TIMPs are found in neurons, Microglia, vascular endothelial cells and leukocytes. The aim of this study was to determine whether circulating levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 are elevated in the plasma of AD patients. We compared AD patients to age- and gender-matched controls as well as to Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) patients. There was constitutive expression of gelatinase A (MMP-2), and gelatinase B (MMP-9), in all the samples as shown by zymographic analysis. Levels of MMP-9 were significantly (P=0.003) elevated in the plasma of AD patients as compared to controls. Plasma levels of MMP-2, TIMP-1 and TIMP-2 were unchanged. There were no significant changes of MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in PD and ALS samples. TIMP-1 and TIMP-2 were significantly correlated with MMP-9 in the AD patients. ApoE genotyping of plasma samples showed that levels of MMP-2, TIMP-1 and TIMP-2 and MMP-9 were not significantly different between the ApoE subgroups. These findings indicate that circulating levels of MMP-9 are increased in AD and may contribute to disease pathology

24. Luca M, Chavez-Ross A, Edelstein-Keshet L, Mogilner A (2003) Chemotactic signaling, Microglia, and Alzheimer's disease senile plaques: is there a connection? Bull.Math.Biol. 65:693-730
    Abstract: Chemotactic cells known as Microglia are involved in the inflammation associated with pathology in Alzheimer's disease (AD). We investigate conditions that lead to aggregation of Microglia and formation of local accumulations of chemicals observed in AD senile plaques. We develop a model for chemotaxis in response to a combination of chemoattractant and chemorepellent signaling chemicals. Linear stability analysis and numerical simulations of the model predict that periodic patterns in cell and chemical distributions can evolve under local attraction, long-ranged repulsion, and other constraints on concentrations and diffusion coefficients of the chemotactic signals. Using biological parameters from the literature, we compare and discuss the applicability of this model to actual processes in AD

25. Luth HJ, Apelt J, Ihunwo AO, Arendt T, Schliebs R (2003) Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice. Brain Res. 977:16-22
    Abstract: Cholinergic dysfunction is a consistent feature of Alzheimer's disease, and the interrelationship between beta-amyloid deposits, inflammation and early cholinergic cell loss is still not fully understood. To characterize the mechanisms by which beta-amyloid and pro-inflammatory cytokines may exert specific degenerating actions on cholinergic cells ultrastructural investigations by electron microscopy were performed in brain sections from transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein and progressively develop beta-amyloid plaques during aging. Both light and electron microscopical investigations of the cerebral cortex of 19-month-old transgenic mice revealed a number of pathological tissue responses in close proximity of beta-amyloid plaques, such as activated Microglia, astroglial proliferation, increased number of fibrous astrocytes, brain edema, degeneration of nerve cells, dendrites and axon terminals. Ultrastructural detection of choline acetyl transferase (ChAT)-immunostaining in cerebral cortical sections of transgenic mice clearly demonstrated degeneration of ChAT-immunoreactive fibres in the environment of beta-amyloid plaques and activated glial cells suggesting a role of beta-amyloid and/or inflammation in specific degeneration of cholinergic synaptic structures

26. McGeer EG, McGeer PL (2003) Inflammatory processes in Alzheimer's disease. Prog.Neuropsychopharmacol.Biol.Psychiatry 27:741-749
    Abstract: Neuroinflammation is a characteristic of pathologically affected tissue in several neurodegenerative disorders. These changes are particularly observed in affected brain areas of Alzheimer's disease (AD) cases. They include an accumulation of large numbers of activated Microglia and astrocytes as well as small numbers of T-cells, mostly adhering to postcapillary venules. Accompanying biochemical alterations include the appearance or up-regulation of numerous molecules characteristic of inflammation and free radical attack. Particularly important may be the complement proteins, acute phase reactants and inflammatory cytokines. These brain phenomena combined with epidemiological evidence of a protective effect of antiinflammatory agents suggest that such agents may have a role to play in treating the disease

27. Melchor JP, Pawlak R, Strickland S (2003) The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J.Neurosci. 23:8867-8871
    Abstract: Accumulation of the amyloid-beta (Abeta) peptide depends on both its generation and clearance. To better define clearance pathways, we have evaluated the role of the tissue plasminogen activator (tPA)-plasmin system in Abeta degradation in vivo. In two different mouse models of Alzheimer's disease, chronically elevated Abeta peptide in the brain correlates with the upregulation of plasminogen activator inhibitor-1 (PAI-1) and inhibition of the tPA-plasmin system. In addition, Abeta injected into the hippocampus of mice lacking either tPA or plasminogen persists, inducing PAI-1 expression and causing activation of Microglial cells and neuronal damage. Conversely, Abeta injected into wild-type mice is rapidly cleared and does not cause neuronal degeneration. Thus, the tPA-plasmin proteolytic cascade aids in the clearance of Abeta, and reduced activity of this system may contribute to the progression of Alzheimer's disease

28. Minnasch P, Yamamoto Y, Ohkubo I, Nishi K (2003) Demonstration of puromycin-sensitive alanyl aminopeptidase in Alzheimer disease brain. Leg.Med.(Tokyo) 5 Suppl 1:S285-S287
    Abstract: Puromycin-sensitive alanyl aminopeptidase (PSA, EC 3.4.11.14) is a member of the ubiquitous aminopeptidase family, which cleaves N-terminal amino acids from proteins. PSA is suggested to function as a trimming protease in the MHC class I pathway, which is activated in brains of Alzheimer disease (AD). We examined the immunohistochemical localization of PSA in brains of AD and control cases using a rabbit anti-PSA. In the control cases, the antiserum revealed staining in a few glial cells and blood vessels. In AD brain, however, intensely stained cells were found richly in the cerebral cortex. Double immunofluorescence studies confirmed that PSA-positive cells were reactive Microglia. Such PSA-positive reactive Microglia tended to locate in and around senile plaques and were sometimes observed to associate with neurons containing neurofibillary tangles. The present result indicates that reactive Microglia express PSA-immunoreactive molecules, probably in association with the pathological conditions of AD

29. Monsonego A, Weiner HL (2003) Immunotherapeutic approaches to Alzheimer's disease. Science 302:834-838
    Abstract: Although neurodegenerative diseases such as Alzheimer's disease are not classically considered mediated by inflammation or the immune system, in some instances the immune system may play an important role in the degenerative process. Furthermore, it has become clear that the immune system itself may have beneficial effects in nervous system diseases considered neurodegenerative. Immunotherapeutic approaches designed to induce a humoral immune response have recently been developed for the treatment of Alzheimer's disease. These studies have led to human trials that resulted in both beneficial and adverse effects. In animal models, it has also been shown that immunotherapy designed to induce a cellular immune response may be of benefit in central nervous system injury, although T cells may have either a beneficial or detrimental effect depending on the type of T cell response induced. These areas provide a new avenue for exploring immune system-based therapy of neurodegenerative diseases and will be discussed here with a primary focus on Alzheimer's disease. We will also discuss how these approaches affect Microglia activation, which plays a key role in therapy of such diseases

30. Morgan D (2003) Antibody therapy for Alzheimer's disease. Expert.Rev.Vaccines. 2:53-59
    Abstract: The economic, social and emotional impact of Alzheimer's dementia is increasing dramatically as greater numbers live to advanced ages. The dearth of effective therapies has led to innovative approaches to treat the disease. This review summarizes the rationale, progress and setbacks regarding the use of antibody-based therapies to treat Alzheimer's disease and discusses future directions for this approach in Alzheimer's and other disorders

31. Munch G, Gasic-Milenkovic J, Dukic-Stefanovic S, Kuhla B, Heinrich K, Riederer P, Huttunen HJ, Founds H, Sajithlal G (2003) Microglial activation induces cell death, inhibits neurite outgrowth and causes neurite retraction of differentiated neuroblastoma cells. Exp.Brain Res. 150:1-8
    Abstract: Activation of glial cells has been proposed to contribute to neuronal dysfunction and neuronal cell death in Alzheimer's disease. In this study, we attempt to determine some of the effects of secreted factors from activated murine N-11 Microglia on viability and morphology of neurons using the differentiated neuroblastoma cell line Neuro2a. Microglia were activated either by lipopolysaccharide (LPS), bacterial cell wall proteoglycans, or advanced glycation endproducts (AGEs), protein-bound sugar oxidation products. At high LPS or AGE concentrations, conditioned medium from Microglia caused neuronal cell death in a dose-dependent manner. At sublethal LPS or AGE concentrations, conditioned media inhibited retinoic acid-induced neurite outgrowth and stimulated retraction of already extended neurites. Among the many possible secreted factors, the contribution of NO or NO metabolites in the cytotoxicity of conditioned medium was investigated. Cell death and changes in neurite morphology were partly reduced when NO production was inhibited by nitric oxide synthase inhibitors. The results suggest that even in the absence of significant cell death, inflammatory processes, which are partly transmitted via NO metabolites, may affect intrinsic functions of neurons such as neurite extension that are essential components of neuronal morphology and thus may contribute to degenerative changes in Alzheimer's disease

32. Murphy A, Sunohara JR, Sundaram M, Ridgway ND, McMaster CR, Cook HW, Byers DM (2003) Induction of protein kinase C substrates, Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP), by amyloid beta-protein in mouse BV-2 Microglial cells. Neurosci.Lett. 347:9-12
    Abstract: Microglial activation by amyloid beta-protein in senile plaques contributes to neurodegeneration in Alzheimer disease. In BV-2 Microglial cells, amyloid beta-protein 1-40 (Abeta 1-40) elicited a dose-dependent increase (3-4 fold) of Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP), two protein kinase C substrates implicated in membrane-cytoskeletal alterations underlying Microglial adhesion, migration, secretion, and phagocytosis. Neither MARCKS nor MRP was induced by the amyloid fragment Abeta 25-35, although both Abeta 1-40 and Abeta 25-35 caused extensive aggregation of BV-2 cells. Interferon-gamma synergistically enhanced the induction by Abeta 1-40 of inducible nitric oxide synthase, but not MARCKS or MRP. Our results suggest that MARCKS and MRP may play important roles in Microglia activated by amyloid peptides

33. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat.Med. 9:448-452
    Abstract: Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with Microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9)

34. Ophir G, Meilin S, Efrati M, Chapman J, Karussis D, Roses A, Michaelson DM (2003) Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice. Neurobiol.Dis. 12:56-64
    Abstract: The allele E4 of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD) and the chronic brain inflammation which is associated with AD is more pronounced in subjects who carry this allele. In the present study, we employed mice transgenic for the human apoE isoforms apoE3 or apoE4 on a null mouse apoE background and intracerebroventricular injection of LPS to investigate the possibility that the regulation of brain inflammation is affected by the apoE genotype. LPS treatment of control mice resulted in activation of brain astrocytes and Microglia whose extent decreased with age. LPS treatment of 6-month-old apoE transgenic and control mice resulted in marked activation of brain astrocytes in the control and apoE3 transgenic mice but had no effect on astrogliosis of age-matched apoE-deficient and apoE4 transgenic mice. In contrast, there were no significant differences between the levels of activated Microglia of the apoE3 and apoE4 transgenic mice following LPS treatment. Immunoblot assays revealed that the apoE4 and apoE3 transgenic mice had the same levels of brain apoE, which were similarly increased following LPS treatment. These results show that LPS-induced astrogliosis in apoE transgenic mice is regulated isoform-specifically by apoE3 and not by apoE4 and suggest that similar mechanisms may mediate the phenotypic expression of the apoE4 genotype in AD and in other neurodegenerative diseases

35. Pahnke J, Walker LC, Schroeder E, Vogelgesang S, Stausske D, Walther R, Warzok RW (2003) Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele. Acta Neuropathol.(Berl) 105:25-29
    Abstract: The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated Microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production

36. Parvathenani LK, Tertyshnikova S, Greco CR, Roberts SB, Robertson B, Posmantur R (2003) P2X7 mediates superoxide production in primary Microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease. J.Biol.Chem. 278:13309-13317
    Abstract: Primary rat Microglia stimulated with either ATP or 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) release copious amounts of superoxide (O(2)(-)*). ATP and BzATP stimulate O(2)(-)* production through purinergic receptors, primarily the P2X(7) receptor. O(2)(-)* is produced through the activation of the NADPH oxidase. Although both p42/44 MAPK and p38 MAPK were activated rapidly in cells stimulated with BzATP, only pharmacological inhibition of p38 MAPK attenuated O(2)(-)* production. Furthermore, an inhibitor of phosphatidylinositol 3-kinase attenuated O(2)(-)* production to a greater extent than an inhibitor of p38 MAPK. Both ATP and BzATP stimulated Microglia-induced cortical cell death indicating this pathway may contribute to neurodegeneration. Consistent with this hypothesis, P2X(7) receptor was specifically up-regulated around beta-amyloid plaques in a mouse model of Alzheimer's disease (Tg2576)

37. Qiu Z, Gruol DL (2003) Interleukin-6, beta-amyloid peptide and NMDA interactions in rat cortical neurons. J.Neuroimmunol. 139:51-57
    Abstract: Neuronal damage in Alzheimer's disease (AD) is thought to involve direct toxicity of beta-amyloid peptide (Abeta) and excitotoxicity involving NMDA receptors (NMDARs) and altered Ca(2+) dynamics. Inflammation agents produced by Microglia or astrocytes and associated with senile plaques such as the cytokine interleukin-6 (IL-6) could also contribute. To investigate this possibility, neuronal damage (lactate dehydrogenase assay, LDH, assay) was measured in cultures of rodent cortical neurons chronically treated with IL-6, Abeta or Abeta plus IL-6 and acutely treated with NMDA. Both Abeta and NMDA produced neuronal damage and this effect was larger with combined treatment. IL-6 did not produce significant neuronal damage but the largest neuronal damage was observed in cultures exposed to all three factors. IL-6 and Abeta enhanced Ca(2+) responses to NMDA and combined treatment produced the largest effect. These results are consistent with a role for interactions between Abeta, NMDA and IL-6 in the neuronal loss in AD

38. Rangon CM, Haik S, Faucheux BA, Metz-Boutigue MH, Fierville F, Fuchs JP, Hauw JJ, Aunis D (2003) Different chromogranin immunoreactivity between prion and a-beta amyloid plaque. Neuroreport 14:755-758
    Abstract: Brain lesions in Creutzfeldt-Jakob disease (CJD) include spongiform change, neuronal loss, amyloid plaques, astrogliosis and Microglial activation. Microglia are thought to play a key role in prion-induced neurodegeneration. However, the intermediate molecules supporting relationships between neurons and Microglia are still unknown. Chromogranins (Cg) are soluble glycophosphoproteins that can activate Microglial cells leading to a neurotoxic phenotype. The immunoreactive patterns of CgA and CgB were investigated in CJD and compared to those observed in Alzheimer's disease. We found that CgB, but not CgA, immunoreactivity was selectively associated with prion protein deposits, whereas CgA was only seen in Abeta plaques. This suggests a specific influence of the constitutive amyloid protein on chromogranin secretion and a role of CgB in the CJD neurodegenerative process

39. Scali C, Giovannini MG, Prosperi C, Bellucci A, Pepeu G, Casamenti F (2003) The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo. Neuroscience 117:909-919
    Abstract: Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and non-steroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this work was to study in vivo whether attenuation of brain inflammatory response to excitotoxic insult by the selective cyclooxygenase-2 inhibitor, rofecoxib, may prevent neurodegeneration, as a contribution to a better understanding of the role inflammation plays in the pathology of Alzheimer's disease. We investigated, by immunohistochemical methods, glia reaction, the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway with an antibody selective for the phosphorylated form of the enzyme and the number of choline acetyltransferase-positive neurons and, by in vivo microdialysis, cortical extracellular levels of acetylcholine following the injection of quisqualic acid into the right nucleus basalis of adult rats. Seven days after injection, a marked reduction in the number of choline acetyltransferase-positive neurons was found, along with an intense glia reaction, selective activation of p38MAPK at the injection site and a significant decrease in the extracellular levels of acetylcholine in the cortex ipsilateral to the injection site. The loss of cholinergic neurons persisted for at least up to 28 days. Rofecoxib (3 mg/kg/day, starting 1 h prior to injection of quisqualic acid) treatment for 7 days significantly attenuated glia activation and prevented the loss of choline acetyltransferase-positive cells and a decrease in cortical acetylcholine release. The prevention of cholinergic cell loss by rofecoxib occurred concomitantly with the inhibition of p38MAPK phosphorylation. Our findings suggest an important role of brain inflammatory reaction in cholinergic degeneration and demonstrate a neuroprotective effect of rofecoxib, presumably mediated through the inhibition of p38MAPK phosphorylation

40. Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE (2003) Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol.Dis. 14:133-145
    Abstract: The present study was designed to examine whether brain inflammation caused by systemic administration of lipopolysaccharides (LPS) alters the expression/processing of amyloid precursor protein (APP) and increases the generation of amyloid beta peptide (Abeta). APPswe transgenic (Tg) mice were treated with either LPS or phosphate-buffered saline (PBS). In LPS-treated APPswe mice, Abeta1-40/42 was 3-fold and APP was 1.8-fold higher than those in PBS-treated mice (P < 0.05) by ELISA, Western blots and immunoprecipitation-mass spectrometry (IP-MS) ProteinChip analysis. Numbers of Abeta- and APP-immunoreactive neurons (Abeta(+) and APP(+) neurons) increased significantly in LPS-treated APPswe mice; APP(+) and Abeta(+) neurons in neocortex were associated with an increased number of F4/80-immunoreactive Microglia (F4/80(+) Microglia) in their anatomical environment. Our findings demonstrate that experimental neuroinflammation increases APP expression/processing and causes intracellular accumulation of Abeta. It remains to be seen whether such events can cause neuronal dysfunction/degeneration and, with time, lead to extracellular Abeta deposits, as they occur in Alzheimer's disease

41. Su Y, Ganea D, Peng X, Jonakait GM (2003) Galanin down-regulates Microglial tumor necrosis factor-alpha production by a post-transcriptional mechanism. J.Neuroimmunol. 134:52-60
    Abstract: The neuropeptide galanin (GAL) is up-regulated following neuronal axotomy or inflammation. Since other neuropeptides act as immunomodulatory agents, we sought to determine whether GAL might affect the murine Microglial cell line BV2, which expresses the GAL2 receptor. Even at very low concentrations, GAL inhibited tumor necrosis factor-alpha (TNF alpha) release but not TNF alpha mRNA levels in LPS-stimulated BV2 cells. Northern blot analysis showed that GAL inhibited the addition of a poly(A) tail, and stability assays showed that it also destabilized TNF alpha mRNA. Thus, GAL inhibits TNF alpha production by a post-transcriptional mechanism that both prevents the efficient addition of the poly(A) tail and accelerates TNF alpha mRNA degradation

42. Takata K, Kitamura Y, Kakimura J, Shibagaki K, Tsuchiya D, Taniguchi T, Smith MA, Perry G, Shimohama S (2003) Role of high mobility group protein-1 (HMG1) in amyloid-beta homeostasis. Biochem.Biophys.Res.Commun. 301:699-703
    Abstract: In Alzheimer's disease (AD), fibrillar amyloid-beta (Abeta) peptides form senile plaques associated with activated Microglia. Recent studies have indicated that Microglial Abeta clearance is facilitated by several activators such as transforming growth factor-beta1 (TGF-beta1). The relationship between Microglia and Abeta formation and deposition is still unclear. In the present study, high mobility group protein-1 (HMG1) inhibited the Microglial uptake of Abeta (1-42) in the presence and absence of TGF-beta1. In addition, HMG1 bound to Abeta (1-42) and stabilized the oligomerization. In AD brains, protein levels of HMG1 were significantly increased in both the cytosolic and particulate fractions, and HMG1 and Abeta were colocalized in senile plaques associated with Microglia. These results suggest that HMG1 may regulate the homeostasis of extracellular Abeta (1-42) and Abeta oligomerization

43. Thaker U, McDonagh AM, Iwatsubo T, Lendon CL, Pickering-Brown SM, Mann DM (2003) Tau load is associated with apolipoprotein E genotype and the amount of amyloid beta protein, Abeta40, in sporadic and familial Alzheimer's disease. Neuropathol.Appl.Neurobiol. 29:35-44
    Abstract: The total amount of hyperphosphorylated tau protein (p-tau load), present as neurofibrillary tangles (NFTs), neuropil threads or plaque neurites, was quantified in the frontal cortex of 109 cases of sporadic Alzheimer's disease (AD) and 35 cases of familial AD due to missense mutations in the presenilin-1, presenilin-2 and amyloid precursor protein genes. p-tau load was inversely correlated with age at onset of illness in both sporadic and familial AD but not with duration of disease. There was no difference in p-tau load between cases of familial AD and others with sporadic AD, matching the familial cases for apolipoprotein E (APO E) genotype. However, p-tau was greater in cases of familial and sporadic AD in the presence of APO E epsilon4 allele and increased with gene dose. Conversely, p-tau load tended to be lower when epsilon2 allele was present. In sporadic AD, tau load was highly significantly correlated with amyloid beta40 (Abeta40), but not Abeta42(43), load. These data indicate that the burden of pathological tau deposited in the brain in both familial and sporadic AD is favoured in the presence of APO E epsilon4 allele and also related to the amount of Abeta40, this also being higher when epsilon4 allele is present. Abeta40 plaques are rich in Microglial cells and it is possible that p-tau pathology in AD is triggered by reaction of Microglial cells to the presence of Abeta40 and not this peptide directly

44. Uryu S, Tokuhiro S, Oda T (2003) beta-Amyloid-specific upregulation of stearoyl coenzyme A desaturase-1 in macrophages. Biochem.Biophys.Res.Commun. 303:302-305
    Abstract: beta-Amyloid peptide (A beta), a major component of senile plaques, the formation of which is characteristic of Alzheimer's disease (AD), is believed to induce inflammation of the brain mediated by Microglia, leading to neuronal cell loss. In this study, we performed an oligonucleotide microarray analysis to investigate the molecular events underlying the A beta-induced activation of macrophages and its specific suppression by the A beta-specific-macrophage-activation inhibitor, RS-1178. Of the approximately 36,000 genes and expressed sequence tags analyzed, eight genes were specifically and significantly upregulated by a treatment with interferon gamma (IFN gamma) and A beta compared to a treatment with IFN gamma alone (p<0.002). We found that the gene for a well-characterized lipogenetic enzyme, stearoyl coenzyme A desaturase-1 (SCD-1), was specifically upregulated by A beta treatment and was suppressed to basal levels by RS-1178. Although the underlying mechanisms remain unknown, our results suggest the presence of a link between AD and SCD-1

45. Veerhuis R, Van Breemen MJ, Hoozemans JM, Morbin M, Ouladhadj J, Tagliavini F, Eikelenboom P (2003) Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human Microglia in vitro. Acta Neuropathol.(Berl) 105:135-144
    Abstract: Pro-inflammatory cytokines released by activated Microglia could be a driving force in Alzheimer's disease (AD) pathology. We evaluated whether the presence of complement factor C1q and serum amyloid P component (SAP) in Abeta deposits is related to Microglial activation. Activated Microglia accumulate in SAP- and C1q-immunoreactive fibrillar amyloid beta (Abeta) plaques in AD temporal cortex. No clustered Microglia are seen in SAP- and C1q-positive circumscript, non-fibrillar, tau-negative Abeta plaques in AD caudate nucleus and non-demented control temporal cortex. In addition, no clustered Microglia were observed in C1q- and SAP-negative, irregular shaped, diffuse plaques in AD caudate nucleus and in non-demented control temporal cortex, which suggests that Microglia are attracted and activated in Abeta deposits of certain fibrillarity that, in addition, have fixed SAP and C1q. Therefore, the effects of Abeta(1-42), SAP and C1q on cytokine secretion by human postmortem Microglia in vitro were assessed. Abeta(1-42) alone had little to no effect. Abeta(1-42) peptides in combination with C1q or C1q and SAP increased Microglial interleukin (IL)-6 secretion four- and eightfold, respectively. Tumor necrosis factor (TNF)-alpha, as well as intracellular IL-1alpha and IL-1beta levels, also increased upon exposure of Microglia to Abeta(1-42)-SAP-C1q complexes. Combined with earlier findings, that amyloid and activated Microglia accumulate at a relatively early stage of cognitive decline in AD patients, this suggests that clustering of activated, cytokine-secreting Microglia in SAP- and C1q-containing Abeta deposits precedes neurodegenerative changes in AD, and thus may provide a "therapeutic window"

46. Vehmas AK, Kawas CH, Stewart WF, Troncoso JC (2003) Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol.Aging 24:321-331
    Abstract: We examined the associations of postmortem neocortical immunoreactivities for Microglia, astrocytes, Abeta and Tau with cognitive changes in clinically characterized subjects with pathological diagnoses (CERAD classification) of definite AD (9), possible AD (15) and age-matched controls (11). By measuring the fractional area (FA) of immunoreactivity, we found that Abeta deposits appear early in the pathogenesis of Abeta, but cannot account for cognitive decline. We found a significant increases in FA for Microglia in possible AD cases (nondemented) compared to controls (P<0.05) and in FA for astrocytes in definite AD (demented) compared to possible AD (P<0.01). Tau immunoreactivity was observed only in the neuropil of definite AD cases (P<0.001). The significant increase in Microglia between controls and AD possible cases suggests that activation of Microglia occurs in the early pathogenesis of AD, whereas the significant association between astrocytic reaction and dementia, suggests that these cells play a role in the late stage of the disease, when dementia develops. Tau immunoreactivity appears as the strongest morphological correlate of dementia

47. Versijpt J, Van Laere K, Dierckx RA, Dumont F, De Deyn PP, Slegers G, Korf J (2003) Scintigraphic visualization of inflammation in neurodegenerative disorders. Nucl.Med.Commun. 24:209-221
    Abstract: In the past few decades, our understanding of the central nervous system has evolved from one of an immune-privileged site, to one where inflammation is pathognomonic for some of the most prevalent and tragic neurodegenerative diseases. Current research indicates that diseases as diverse as multiple sclerosis, stroke and Alzheimer's disease exhibit inflammatory processes that contribute to cellular dysfunction or loss. Inflammation, whether in the brain or periphery, is almost always a secondary response to a primary pathogen. In head trauma, for example, the blow to the head is the primary event. What typically concerns the neurologist and neurosurgeon more, however, is the secondary inflammatory response that will ensue and likely cause more neuron loss than the initial injury. This paper reviews the basic neuroinflammatory mechanisms, the potential neurotoxic mediators during activation of Microglia, the brain resident macrophages, and their role in neurodegeneration. Alzheimer's disease is taken as a prototype for exploring these mechanisms, as it expresses more than 40 inflammatory mediators, it is the most extensively studied disorder in terms of immune-related pathogenesis, and because of its importance as the most prevalent type of dementia. Tools for the visualization of these neuroinflammatory processes, both structural and mainly functional, are critically reviewed and discussed

48. Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, Achten E, Slegers G, Dierckx RA, Korf J (2003) Assessment of neuroinflammation and Microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur.Neurol. 50:39-47
    Abstract: OBJECTIVES: Inflammation contributes to degeneration in Alzheimer's disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [(123)I]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, the latter being expressed on Microglia (brain resident macrophages) and upregulated under inflammatory circumstances. The objectives were to assess AD inflammation by detecting [(123)I]iodo-PK11195 uptake changes and investigate how uptake values relate with perfusion SPECT and neuropsychological findings. METHODS: Ten AD and 9 control subjects were included. [(123)I]iodo-PK11195 SPECT images were realigned into stereotactic space where binding indices, normalized on cerebellar uptake, were calculated. RESULTS: The mean [(123)I]iodo-PK11195 uptake was increased in AD patients compared with controls in nearly all neocortical regions; however, statistical significance was only reached in the frontal and right mesotemporal regions. Significant correlations were found between regional increased [(123)I]iodo-PK11195 uptake and cognitive deficits. CONCLUSIONS: [(123)I]iodo-PK11195 is a cellular disease activity marker and allows in vivo assessment of Microglial inflammation in AD

49. Watkins D (2003) Brain not inflamed? Alzheimer's may not be an inflammation after all. Sci.Am. 289:24-26

50. Wegiel J, Imaki H, Wang KC, Wegiel J, Wronska A, Osuchowski M, Rubenstein R (2003) Origin and turnover of Microglial cells in fibrillar plaques of APPsw transgenic mice. Acta Neuropathol.(Berl) 105:393-402
    Abstract: Activated Microglial cells are an integral component of fibrillar plaques in brains of subjects with Alzheimer's disease (AD) and in brains of transgenic mice overexpressing amyloidogenic fragments of human amyloid precursor protein (APP). The aim of this ultrastructural study of fibrillar plaques was to characterize the origin of Microglial cells involved in cored plaque formation. Computer-aided three-dimensional reconstruction of plaques and microvessels in APPsw transgenic mice shows perivascular development of cored plaques. Perivascular location of almost all examined plaques and the infiltration at the interface between vessels and plaques with cells of monocyte/Microglia lineage indicates that plaques are formed by inflammatory cells of blood origin. The increase in the number of Microglial cells from 1 or 2 in an early plaque to more than 100 in a several-month-old plaque does not result in plaque degradation, but is associated with amyloid core growth and progression of neuronal degeneration, and suggests that recruitment of inflammatory cells of blood origin sustains plaque growth. Infiltration of the plaque with cells of blood origin and degeneration of 10-46% of inflammatory cells in large plaques, which is especially frequent at the interface between capillary wall and plaque, suggest their accelerated turnover

51. White AR, Maher F, Brazier MW, Jobling MF, Thyer J, Stewart LR, Thompson A, Gibson R, Masters CL, Multhaup G, Beyreuther K, Barrow CJ, Collins SJ, Cappai R (2003) Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation. Brain Res. 966:231-244
    Abstract: The Alzheimer's disease Abeta peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Abeta and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-beta (Abeta), the fibrillar prion peptides PrP106-126 and PrP178-193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. Specificity was shown by a lack of change to amyloid precursor-like protein 1, tau-1 and cellular prion protein (PrP(c)) levels. APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that PrP106-126 and the non-toxic but fibril-forming PrP178-193 increased APP levels in cultures derived from both wild-type and PrP(c)-deficient mice indicating that fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and irrespective of parental protein expression. Fibrillar PrP106-126 and Abeta peptides bound recombinant APP and APLP2 suggesting the accumulation of these proteins was mediated by direct binding to the fibrillated peptide. This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18-146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders

52. Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, Ugen KE, Gordon MN, Morgan D (2003) Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with Microglial activation. J.Neurosci. 23:3745-3751
    Abstract: Active immunization against the beta-amyloid peptide (Alphabeta) with vaccines or passive immunization with systemic monoclonal anti-Abeta antibodies reduces amyloid deposition and improves cognition in APP transgenic mice. In this report, intracranial administration of anti-Alphabeta antibodies into frontal cortex and hippocampus of Tg2576 transgenic APP mice is described. The antibody injection resulted initially in a broad distribution of staining for the antibody, which diminished over 7 d. Although no loss of immunostaining for deposited Abeta was apparent at 4 hr, a dramatic reduction in the Alphabeta load was discernible at 24 hr and was maintained at 3 and 7 d. A reduction in the thioflavine-S-positive compact plaque load was delayed until 3 d, at which time Microglial activation also became apparent. At 1 week after the injection, Microglial activation returned to control levels, whereas Alphabeta and thioflavine-S staining remained reduced. The results from this study suggest a two-phase mechanism of anti-Alphabeta antibody action. The first phase occurs between 4 and 24 hr, clears primarily diffuse Alphabeta deposits, and is not associated with observable Microglial activation. The second phase occurs between 1 and 3 d, is responsible for clearance of compact amyloid deposits, and is associated with Microglial activation. The results are discussed in the context of other studies identifying coincident Microglial activation and amyloid removal in APP transgenic animals

53. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J.Neurosci. 23:7504-7509
    Abstract: Alzheimer's disease (AD) is characterized by a Microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Nonsteroidal anti-inflammatory drug (NSAID) treatment reduces AD risk, slows disease progression, and reduces Microglial activation; however, the basis of these effects is unknown. We report that treatment of 11-month-old Tg2576 mice overexpressing human amyloid precursor protein (APP) with the NSAID ibuprofen for 16 weeks resulted in the dramatic and selective reduction of SDS-soluble beta-amyloid (Abeta)42, whereas it had smaller effects on SDS-soluble Abeta40 levels. Ibuprofen treatment resulted in 60% reduction of amyloid plaque load in the cortex of these animals. In vitro studies using APP-expressing 293 cells showed that ibuprofen directly affected APP processing, specifically reducing the production of Abeta42. Ibuprofen treatment resulted in a significant reduction in Microglial activation in the Tg2576 mice, as measured by CD45 and CD11b expression. NSAIDs activate the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma); however, a potent agonist of this receptor, pioglitazone, only modestly reduced SDS-soluble Abeta levels and did not affect amyloid plaque burden or Microglia activation, indicating that PPARgamma activation is not involved in the Abeta lowering effect of NSAIDs. These data show that chronic NSAID treatment can reduce brain Abeta levels, amyloid plaque burden, and Microglial activation in an animal model of Alzheimer's disease

54. Aisen PS (2002) The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease. Lancet Neurol. 1:279-284
    Abstract: Genetic evidence suggests that generation of amyloid beta peptide is the pivotal step in the pathophysiology of Alzheimer's disease (AD). The mechanism by which this peptide induces neurodegeneration may involve inflammatory processes. Pharmacological suppression of inflammation may therefore ameliorate the neuropathology. Basic research studies provide substantial evidence that inflammatory processes present in the brains of patients with AD are destructive, and that anti-inflammatory drugs can provide protection. Furthermore, epidemiological studies suggest that anti-inflammatory drugs reduce the risk of AD. However, there is not yet any strong evidence from completed randomised controlled trials that anti-inflammatory treatment is beneficial. Large trials of glucocorticoid therapy, hydroxychloroquine, and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of AD have so far been disappointing. Several studies, including a large primary prevention trial with NSAIDs, are still in progress. Major issues of selection of patients, drug regimen, and duration of treatment remain unresolved

55. Ali-Khan Z (2002) Searching for an in vivo site for nascent amyloid fibril formation. J.Alzheimers.Dis. 4:105-114

56. Apelt J, Lessig J, Schliebs R (2002) Beta-amyloid-associated expression of intercellular adhesion molecule-1 in brain cortical tissue of transgenic Tg2576 mice. Neurosci.Lett. 329:111-115
    Abstract: To study the relationship of beta-amyloid-mediated micro- and astrogliosis and inflammation-induced proteins including intercellular adhesion molecule (ICAM-1), brain tissue from transgenic Tg2576 mice expressing the Swedish mutation of the human amyloid precursor protein were examined for ICAM-1 expression. Immunocytochemistry demonstrated a diffuse immunostaining of ICAM-1 in the corona around fibrillary beta-amyloid plaques and an upregulation of ICAM-1 in activated Microglial cells located in close proximity to the plaques, an ICAM-1 distribution pattern that partly mimics the situation in the brain of Alzheimer patients. The developmental time course revealed that the rate of cortical ICAM-1 induction was somewhat behind that of the progression of beta-amyloid plaque deposition. The Microglial expression of ICAM-1 is a further indicator of the presence of inflammatory reactions in aged transgenic Tg2576 mouse brain, and may be a result of plaque-mediated astrocytic interleukin-1beta upregulation

57. Arelin K, Kinoshita A, Whelan CM, Irizarry MC, Rebeck GW, Strickland DK, Hyman BT (2002) LRP and senile plaques in Alzheimer's disease: colocalization with apolipoprotein E and with activated astrocytes. Brain Res.Mol.Brain Res. 104:38-46
    Abstract: The low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor which is present on senile plaques in Alzheimer's disease (AD). It is suggested to play an important role in the balance between amyloid beta (Abeta) synthesis and clearance mechanisms. One of its ligands, apolipoprotein E (apoE), is also present on senile plaques and has been implicated as a risk factor for AD, potentially affecting the deposition, fibrillogenesis and clearance of Abeta. Using immunohistochemistry we show that LRP was present only on cored, apoE-containing senile plaques, in both PDAPP transgenic mice and human AD brains. We detected strong LRP staining in neurons and in reactive astrocytes, and immunostaining of membrane-bound LRP showed colocalization with fine astrocytic processes surrounding senile plaques. LRP was not present in plaques in young transgenic mice or in plaques of APOE-knockout mice. As LRP ligands associated with Abeta deposits in AD brain may play an important role in inducing levels of LRP in both neurons and astrocytes, our findings support the idea that apoE might be involved in upregulation of LRP (present in fine astrocytic processes) and act as a local scaffolding protein for LRP and Abeta. The upregulation of LRP would allow increased clearance of LRP ligands as well as clearance of Abeta/ApoE complexes

58. Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, Hyman BT (2002) Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J.Neurosci. 22:7873-7878
    Abstract: Transgenic (Tg) mouse models overexpressing amyloid precursor protein (APP) develop senile plaques similar to those found in Alzheimer's disease in an age-dependent manner. Recent reports demonstrated that immunotherapy is effective at preventing or removing amyloid-beta deposits in the mouse models. To characterize the mechanisms involved in clearance, we used antibodies of either IgG1 (10d5) or IgG2b (3d6) applied directly to the brains of 18-month-old Tg2576 or 20-month-old PDAPP mice. Both 10d5 and 3d6 led to clearance of 50% of diffuse amyloid deposits in both animal models within 3 d. Fc receptor-mediated clearance has been shown to be important in an ex vivo assay showing antibody-mediated clearance of plaques by Microglia. We now show, using in vivo multiphoton microscopy, that FITC-labeled F(ab')2 fragments of 3d6 (which lack the Fc region of the antibody) also led to clearance of 45% of the deposits within 3 d, similar to the results obtained with full-length 3d6 antibody. This result suggests that direct disruption of plaques, in addition to Fc-dependent phagocytosis, is involved in the antibody-mediated clearance of amyloid-beta deposits in vivo. Dense-core deposits that were not cleared were reduced in size by approximately 30% with full-length antibodies and F(ab')2 fragments 3 d after a topical treatment. Together, these results indicate that clearance of amyloid deposits in vivo may involve, in addition to Fc-dependent clearance, a non-Fc-mediated disruption of plaque structure

59. Bamberger ME, Landreth GE (2002) Inflammation, apoptosis, and Alzheimer's disease. Neuroscientist. 8:276-283
    Abstract: The pathophysiology of Alzheimer's disease (AD) involves the deposition of amyloid in the brain and the extensive loss of neurons. The mechanisms subserving neuronal death in the disease remain unclear, although it has been postulated that this is due to apoptosis. There is compelling evidence that inflammatory processes play a role in disease progression and pathology. Amyloid plaque deposition is accompanied by the association of Microglia with the senile plaque, and this interaction stimulates these cells to undergo phenotypic activation and the subsequent elaboration of proinflammatory and neurotoxic products. This review focuses on the mechanisms by which neurons are lost in AD and the role Microglial proinflammatory products play in neuronal death

60. Bi X, Gall CM, Zhou J, Lynch G (2002) Uptake and pathogenic effects of amyloid beta peptide 1-42 are enhanced by integrin antagonists and blocked by NMDA receptor antagonists. Neuroscience 112:827-840
    Abstract: Many synapses contain two types of receptors - integrins and N-methyl-D-aspartate (NMDA) receptors - that have been implicated in peptide internalization. The present studies tested if either class is involved in the uptake of the 42-residue form of amyloid beta peptide (Abeta1-42), an event hypothesized to be of importance in the development of Alzheimer's disease. Cultured hippocampal slices were exposed to Abeta1-42 for 6 days in the presence or absence of soluble Gly-Arg-Gly-Asp-Ser-Pro, a peptide antagonist of Arg-Gly-Asp (RGD)-binding integrins, or the disintegrin echistatin. Abeta uptake, as assessed with immunocytochemistry, occurred in 42% of the slices incubated with Abeta peptide alone but in more than 80% of the slices co-treated with integrin antagonists. Uptake was also found in a broader range of hippocampal subfields in RGD-treated slices. Increased sequestration was accompanied by two characteristics of early stage Alzheimer's disease: elevated concentrations of cathepsin D immunoreactivity and activation of Microglia. The selective NMDA receptor antagonist D-(-)-2-amino-5-phosphonovalerate completely blocked internalization of Abeta, up-regulation of cathepsin D, and activation of Microglia. Our results identify two classes of receptors that cooperatively regulate the internalization of Abeta1-42 and support the hypothesis that characteristic pathologies of Alzheimer's disease occur once critical intraneuronal Abeta concentrations are reached

61. Bondolfi L, Calhoun M, Ermini F, Kuhn HG, Wiederhold KH, Walker L, Staufenbiel M, Jucker M (2002) Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. J.Neurosci. 22:515-522
    Abstract: APP23 transgenic mice express mutant human amyloid precursor protein and develop amyloid plaques predominantly in neocortex and hippocampus progressively with age, similar to Alzheimer's disease. We have previously reported neuron loss in the hippocampal CA1 region of 14- to 18-month-old APP23 mice. In contrast, no neuron loss was found in neocortex. In the present study we have reinvestigated neocortical neuron numbers in adult and aged APP23 mice. Surprisingly, results revealed that 8-month-old APP23 mice have 13 and 14% more neocortical neurons compared with 8-month-old wild-type and 27-month-old APP23 mice, respectively. In 27-month-old APP23 mice we found an inverse correlation between amyloid load and neuron number. These results suggest that APP23 mice have more neurons until they develop amyloid plaques but then lose neurons in the process of cerebral amyloidogenesis. Supporting this notion, we found more neurons with a necrotic-apoptotic phenotype in the neocortex of 24-month-old APP23 mice compared with age-matched wild-type mice. Stimulated by recent reports that demonstrated neurogenesis after targeted neuron death in the mouse neocortex, we have also examined neurogenesis in APP23 mice. Strikingly, we found a fourfold to sixfold increase in newly produced cells in 24-month-old APP23 mice compared with both age-matched wild-type mice and young APP23 transgenic mice. However, subsequent cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were Microglial and to a lesser extent astroglial cells. We conclude that cerebral amyloidosis in APP23 mice causes a modest neuron loss in neocortex and induces marked gliogenesis

62. Brown CM, Wright E, Colton CA, Sullivan PM, Laskowitz DT, Vitek MP (2002) Apolipoprotein E isoform mediated regulation of nitric oxide release. Free Radic.Biol.Med. 32:1071-1075
    Abstract: Progressive dysfunction and death of neurons in Alzheimer's dementia is enhanced in patients carrying one or more APOE4 alleles who also display increased presence of oxidative stress markers. Modulation of oxidative stress is a nontraditional and physiologically relevant immunomodulatory function of apolipoprotein E (apoE). Stimulated peritoneal macrophages from APOE-transgenic replacement (APOE-TR) mice expressing only human apoE3 or human apoE4 protein isoforms were utilized as mouse models to investigate the role of apoE protein isoforms and gender in the regulation of oxidative stress. Macrophages from male APOE4/4-TR mice produced significantly higher levels of nitric oxide than from male APOE3/3-TR mice, while macrophages from female APOE3/3-TR and female APOE4/4-TR mice produced the similar levels of nitric oxide. Primary cultures of Microglial cells of APOE4 transgenic mice also produced significantly more nitric oxide than Microglia from APOE3 transgenic mice. These data suggest a potentially novel mechanism for gender-dependent and apoE isoform-dependent immune responses that parallel the genetic susceptibility of APOE4 carriers for the development of Alzheimer's disease

63. Butterfield DA, Griffin S, Munch G, Pasinetti GM (2002) Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists. J.Alzheimers.Dis. 4:193-201
    Abstract: Alzheimer's disease (AD) brain is characterized by excess deposition of amyloid beta-peptide (Abeta), particularly the 42-amino acid peptide [Abeta(1-42)] and by extensive oxidative stress. Several sources of the oxidative stress and inflammatory cascades are likely, including that induced by advanced glycation end products, Microglial activation, and by Abeta(1-42) and its sequelae. This review briefly examines each of these sources of oxidative stress and inflammation in AD brain and discusses their potential roles in the clinical progression of AD dementia

64. Calingasan NY, Erdely HA, Anthony AC (2002) Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol.Aging 23:31-39
    Abstract: Chronic neuroinflammatory processes including glial activation may play a role in the pathogenesis of Alzheimer's disease (AD). The immune and inflammatory mediator CD40 ligand (CD40L) can augment the activation of cultured Microglia by amyloid beta-protein (Abeta) and promote neuron death. We investigated whether CD40L is increased in AD and in animal models of AD and neuroinflammation. In the frontal cortex of elderly, non-AD controls, CD40L immunoreactivity was found in the glial limiting membrane, astrocytes, and vascular profiles in gray and white matter. In AD, intense CD40L immunoreactivity occurred in hypertrophied astrocytes throughout the frontal cortex. The majority of CD40L-immunoreactive astrocytes in the gray matter occurred within, or at the periphery of, Abeta(1-42)-immunoreactive plaques. A semiquantitative analysis revealed a three-fold elevation in the number of CD40L-immunoreactive astrocytes in AD compared to controls. The cortex and hippocampus from 6 and 12 month-old amyloid precursor protein/presenilin 1 transgenic mice exhibited numerous neuritic plaques and CD40L-positive astrocytes, which were not detected in non-transgenic controls. In adult rats, little or no CD40L staining occurred in astrocytes of the intact brain, whereas intrastriatal excitotoxic or stab wound lesions produced a strong CD40L immunoreactivity that was more segregated than glial fibrillary acidic protein. These findings indicate that astrocytes are the predominant source of CD40L in brain, and are consistent with the proposed role of CD40L-mediated neurotoxic inflammation in AD

65. Casal C, Serratosa J, Tusell JM (2002) Relationship between beta-AP peptide aggregation and Microglial activation. Brain Res. 928:76-84
    Abstract: We compared the relationship between the state of aggregation of two peptides (beta-AP 25-35 and beta-AP 1-42) and Microglial activation. After 7 days at 37 degrees C beta-AP 25-35 was in an amorphous state and did not activate Microglial cells. In the same conditions, aggregated beta-AP 1-42 activated these cells and caused changes in Microglial ramification, increasing the proliferation index and inducing tumor necrosis factor alpha (TNF alpha) release. Neither peptide induced a release of nitric oxide (NO). As the toxicity of beta-AP peptides in cell culture is associated with the formation of amyloid fibrils, we also examined the toxicity of both peptides in Microglial cell cultures and in PC 12 cell cultures. The results suggest that the two beta-AP fragments studied have similar neurotoxic effects but different pro-inflammatory activities

66. Colton CA, Brown CM, Cook D, Needham LK, Xu Q, Czapiga M, Saunders AM, Schmechel DE, Rasheed K, Vitek MP (2002) APOE and the regulation of Microglial nitric oxide production: a link between genetic risk and oxidative stress. Neurobiol.Aging 23:777-785
    Abstract: The mechanism linking the APOE4 gene with increased susceptibility for Alzheimer's disease (AD) and poorer outcomes following closed head injury and stroke is unknown. One potential link is activation of the innate immune system in the CNS. Our previously published data demonstrated that apolipoprotein E regulates production of nitric oxide, a critical cytoactive factor released by immune active macrophages. To determine if immune regulation is different in the presence of apolipoprotein E4 compared to apolipoprotein E3, we have measured NO production by peritoneal and CNS macrophages (Microglia) cultured from transgenic mice that only express the human apoE4 or apoE3 protein isoform. Significantly more NO was produced in APOE4 mice compared to APOE3 transgenic mice that only express human apoE3 protein. Similarly, monocyte derived macrophages from humans carrying APOE4 gene alleles also produce significantly greater NO than those individuals with APOE3. The mechanism for this isoform-specific difference in NO production is not known and multiple sites in the NO production pathway may be affected. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein are not significantly different between the APOE3 and APOE4 mice, suggesting that induction of iNOS is not a primary cause of the increased NO production in APOE4 animals. One alternative regulatory mechanism that demonstrates isoform specificity is arginine transport, which is greater in Microglia from APOE4 transgenic mice compared to Microglia from APOE3 mice. Increased transport is consistent with an increased production of NO and may reflect a direct or indirect effect of the APOE genotype on Microglial arginine uptake and Microglial activation in general. Overall, greater NO production in APOE4 carriers where characteristically high levels of oxidative/nitrosative stress are found in diseases such as AD provides a mechanism that potentially explains the genetic association between APOE4 and human diseases

67. Colton CA, Brown CM, Czapiga M, Vitek MP (2002) Apolipoprotein-E allele-specific regulation of nitric oxide production. Ann.N.Y.Acad.Sci. 962:212-225
    Abstract: Cognitive decline and dementia are key features of Alzheimer's disease (AD) that result from failure of neuronal function. Affected neurons demonstrate indices of nitrosative stress resulting from changes in nitric oxide (NO) mediated redox balance. Neurofibrillary tangles, a characteristic neuropathologic feature of AD, and dysfunctional neurons frequently display 3-nitrotyrosine or other markers of nitrosative stress and immunoreactive nitric oxide synthase (NOS), suggesting that NOS-containing neurons are affected in AD. Our previous studies showed that apolipoprotein E treatment of macrophages increased NO production. Using transgenic mouse models expressing human apoE2, apoE3, or apoE4 protein isoforms and no mouse apoE, we now report an isoform specific difference in Microglial NO production. Mice expressing the apoE4 protein isoform have a greater NO production than mice expressing the apoE3 protein isoform. The supply of arginine, the sole substrate for NOS, is dependent on cationic amino acid transporters (CATs) that also demonstrate a similar pattern of apoE isoform dependency. Although arginine transport is greater in APOE4 Microglia, this effect is not limited to tissue macrophages. Cortical neurons in primary culture from APOE4 transgenic mice exhibit a similar increase in arginine uptake over neurons cultured from APOE3 mice. The inappropriate levels of arginine transport and of NO in the presence of the APOE4 compared to the APOE3 gene and its products are likely to have significant impact in the CNS

68. Combarros O, Infante J, Llorca J, Pena N, Fernandez-Viadero C, Berciano J (2002) The myeloperoxidase gene in Alzheimer's disease: a case-control study and meta-analysis. Neurosci.Lett. 326:33-36
    Abstract: Myeloperoxidase (MPO) presence has been demonstrated in Microglia associated with senile plaques, and contributes to Alzheimer's disease (AD) pathology through oxidation-induced damage. Recently, a functional biallelic (G/A) polymorphism in the promotor region (-463) of the MPO gene has been associated with susceptibility to AD, but the reports of this association have been inconsistent. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 327 control subjects was performed to test this association. The current study does not demonstrate any significant difference in MPO genotype or allele frequencies between AD patients and controls. A meta-analysis of all studies available gave a non-significant (P=0.83) odds ratio of 1.02 for the MPO GG genotype. Our study in the Spanish population as well as the meta-analysis argue against the hypothesis that the MPO gene is causally related to AD

69. Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El Khoury JB (2002) CD36, a class B scavenger receptor, is expressed on Microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am.J.Pathol. 160:101-112
    Abstract: A pathological hallmark of Alzheimer's disease is the senile plaque, composed of beta-amyloid fibrils, Microglia, astrocytes, and dystrophic neurites. We reported previously that class A scavenger receptors mediate adhesion of Microglia and macrophages to beta-amyloid fibrils and oxidized low-density lipoprotein (oxLDL)-coated surfaces. We also showed that CD36, a class B scavenger receptor and an oxLDL receptor, promotes H(2)O(2) secretion by macrophages adherent to oxLDL-coated surfaces. Whether CD36 is expressed on Microglia, and whether it plays a role in secretion of H(2)O(2) by Microglia interacting with fibrillar beta-amyloid is not known. Using fluorescence-activated cell sorting analysis and immunohistochemistry, we found that CD36 is expressed on human fetal Microglia, and N9-immortalized mouse Microglia. We also found that CD36 is expressed on Microglia and on vascular endothelial cells in the brains of Alzheimer's disease patients. Bowes human melanoma cells, which normally do not express CD36, gained the ability to specifically bind to surfaces coated with fibrillar beta-amyloid when transfected with a cDNA encoding human CD36, suggesting that CD36 is a receptor for fibrillar beta-amyloid. Furthermore, two different monoclonal antibodies to CD36 inhibited H(2)O(2) production by N9 Microglia and human macrophages adherent to fibrillar beta-amyloid by approximately 50%. Our data identify a role for CD36 in fibrillar beta-amyloid-induced H(2)O(2) production by Microglia, and imply that CD36 can mediate binding to fibrillar beta-amyloid. We propose that similar to their role in the interaction of macrophages with oxLDL, class A scavenger receptors and CD36 play complimentary roles in the interactions of Microglia with fibrillar beta-amyloid

70. Cui Y, Le Y, Yazawa H, Gong W, Wang JM (2002) Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease. J.Leukoc.Biol. 72:628-635
    Abstract: Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by the presence of multiple senile plaques in the brain tissue, which are also associated with considerable inflammatory infiltrates. Although the precise mechanisms of the pathogenesis of AD remain to be determined, the overproduction and precipitation of a 42 amino acid form of beta amyloid (Abeta(42)) in plaques have implicated Abeta in neurodegeneration and proinflammatory responses seen in the AD brain. Our recent studies revealed that the activation of formyl peptide receptor-like 1 (FPRL1), a seven-transmembrane, G-protein-coupled receptor, by Abeta(42) may be responsible for accumulation and activation of mononuclear phagocytes (monocytes and Microglia). We further found that upon binding FPRL1, Abeta(42) was rapidly internalized into the cytoplasmic compartment in the form of Abeta(42)/FPRL1 complexes. Persistent exposure of FPRL1-expressing cells to Abeta(42) resulted in intracellular retention of Abeta(42)/FPRL1 complexes and the formation of Congo-red-positive fibrils in mononuclear phagocytes. Our observations suggest that FPRL1 may not only mediate the proinflammatory activity of Abeta(42) but also actively participate in Abeta(42) uptake and the resultant fibrillar formation. Therefore, FPRL1 may constitute an additional molecular target for the development of therapeutic agents for AD

71. Czlonkowska A, Kurkowska-Jastrzebska I (2002) [The role of inflammatory reaction in Alzheimer's disease and neurodegenerative processes]. Neurol.Neurochir.Pol. 36:15-23
    Abstract: Recent studies state that specific inflammatory mechanisms contribute to neurodegeneration. The theory is based on laboratory evidence of local upregulation of inflammatory cytokines (ex. IL-1, IL-6), acute phase proteins (ex. alpha 1-antitrypsin), activation of the complement cascade and accumulation of Microglia in damaged regions in AD. In addition epidemiologic studies suggest that anti-inflammatory treatment provides some protection from AD. The first trials with prednisone fail to show any positive influence in AD patients. The alternative therapies are now considered with nonsteroid anti-inflammatory drugs, colchicine, cyclophosphamide. The anti-inflammatory treatment gives hope for slowing progression of the disease and decline of AD incidence

72. DeGiorgio LA, Manuelidis L, Bernstein JJ (2002) Transient appearance of amyloid precursor protein plaques in the brain of thymectomized rats after human leptomeningeal cell grafts. Neurosci.Lett. 322:62-66
    Abstract: Cells cultured from Alzheimer disease leptomeninges or skin were grafted into the cortex of adult thymectomized rats. At 3 days post-implant, plaque-like aggregates were found in the cortex, corpus callosum, septum and caudate nucleus. These structures were immunopositive for human amyloid precursor protein (APP), human amyloid beta peptide (Abeta), cathepsin D, apolipoprotein E and ubiquitin. Aberrant tau+ neurites, reactive astrocytes and Microglia were associated with many aggregates. Although birefringent amyloid occupied the central area of most aggregates, these structures had disappeared by l month post-implant. Abeta and APP produced by grafted non-neural human cells can penetrate rat brain and form plaque-like structures, which can be effectively cleared by the rat

73. Eikelenboom P, Hoogendijk WJ, Jonker C, van Tilburg W (2002) Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer's disease. J.Psychiatr.Res. 36:269-280
    Abstract: Pathological, genetic and epidemiological studies support the opinion that inflammatory mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recent pathological and neuroradiological (PET) data show that activation of Microglia is an early pathogenic event that precedes the process of severe neuropil destruction in AD brains. In this paper we review the evidence that inflammatory mediators can play a pathogenic role in some behavioural disorders frequently encountered during the clinical course in AD patients. Motivational disturbances are the most striking of the depressive symptoms in AD and can be present in a preclinical stage of the disease. Experimental animal studies and clinical trials in humans have shown that cytokines can induce similar symptoms which were described as 'sickness behaviour' or 'depressive-like' state. Delirious states are frequently observed in more advanced stages of dementia. Delirium is generally considered the result of an imbalance in neurotransmitter systems with severe deficits of the cholinergic systems. Animal studies show that pro-inflammatory cytokines, such as interleukin-1, induce a reduced activity of the cholinergic system. In AD, the release of cytokines would exacerbate any already existing disturbances in the cholinergic neurotransmission. This could explain the susceptibility of demented patients to delirium provoked by a wide variety of trivial incidents that are accompanied by an acute phase response. The data reviewed in this paper suggest that it could be worthwhile employing a neuroimmunological approach to study at molecular level the pathogenesis of a broad spectrum of behavioural disturbances common in the clinical course of AD patients

74. Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A (2002) Neuroinflammation in Alzheimer's disease and prion disease. Glia 40:232-239
    Abstract: Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular depo