Alzheimer Disease: Van Eldik LJ

Van Eldik LJ. · No affiliation provided · Neurochem Int. · Pubmed #11578767 No free full text.

This publication has no abstract.

Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin Watterson D. · Center for Drug Discovery and Chemical Biology, Northwestern University Chicago, Illinois 60611, USA. · Int Rev Neurobiol. · Pubmed #17678967 No free full text.

Abstract: Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation-provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of proinflammatory cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function-driven and target-based, that show promise for development of neuroinflammation-targeted, disease-modifying therapeutics for multiple neurodegenerative disorders.

Manelli AM, Stine WB, Van Eldik LJ, LaDu MJ. · Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA. · J Mol Neurosci. · Pubmed #15181252 No free full text.

Abstract: Abnormalities in the processing of amyloid precursor protein to amyloid-beta (Abeta) are causal factors, and the presence of the epsilon4 allele of apolipoprotein E (apoE) is the primary risk factor for Alzheimer's disease (AD). Based, at least in part, on these genetics, the potential structural and functional interactions between these two proteins are the focus of our research. To understand the nature of the physical interactions between apoE and Abeta, we initially utilized gel-shift assays to demonstrate that native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with Abeta that is more abundant than the apoE4:Abeta complex. We further demonstrated that exogenous apoE3 but not E4 prevents Abeta-induced neurotoxicity by a process that requires apoE receptors. In addition, both exogenous apoE3 and E4 prevent Abeta-induced, glial-mediated inflammation, also via a process that requires apoE receptors. These functional effects all occur at a molar ratio of apoE to Abeta of 1:30. Because the biological activities for both apoE and Abeta are profoundly influenced by their isoform and conformation, respectively, we further investigated the idea that apoE3 and E4 differentially interact with particular aggregation species of Abeta1-42. Our overall hypothesis is that apoE has two general functions in relation to Abeta. First, apoE interacts with oligomeric Abeta via an apoE receptor-mediated process to inhibit neurotoxicity and neuroinflammation (apoE3 > apoE4) a process possibly related to binding and clearance of apoE3:oligomer complexes. Second, apoE facilitates the deposition of Abeta as amyloid (apoE4 > apoE3). We will continue to investigate the effect of apoE isoform and Abeta conformation on the structural and functional interactions between these two proteins in relation to the pathogenesis of AD.

Van Eldik LJ, Koppal T, Watterson DM. · Department of Cell and Molecular Biology, Northwestern Drug Discovery Program, Northwestern University Medical School, Chicago, Illinois 06011-3008, USA. · Alzheimer Dis Assoc Disord. · Pubmed #12070358 No free full text.

Abstract: The drug discovery and the drug development processes represent a continuum of recursive activities that range from initial drug target identification to final Food and Drug Administration approval and marketing of a new therapeutic. Drug discovery, as its name implies, is more exploratory and less focused in many cases, whereas drug development has a clinically defined endpoint and a specific disease goal. Academia has historically made major contributions to this process at the early discovery phases. However, current trends in the organization of the pharmaceutical industry suggest an expanded role for academia in the near future. Megamergers among major pharmaceutical corporations indicate their movement toward a focus on end-stage clinical trials, manufacturing, and marketing. There has been a parallel increase in outsourcing of intermediate steps to specialty small pharmaceutical, biotechnology, and contract service companies. The new paradigm suggests that academia will play an increasingly important role at the proof-of-principle stage of basic and clinical drug discovery research, in training the future skilled work force, and in close partnerships with small pharmaceutical and biotechnology companies. However, academic drug discovery research faces a set of barriers to progress, the relative importance of which varies with the home institution and the details of the research area. These barriers fall into four general categories: (1) the historical administrative structure and environment of academia; (2) the structure and emphasis of peer review panels that control research funding by government and private agencies; (3) the organization and operation of the academic infrastructure; and (4) the structure and availability of specialized resources and information management. Selected examples of barriers to drug discovery and drug development research and training in academia are presented, as are some specific recommendations designed to minimize or circumvent these barriers. In some cases, precedents established by other disease-focused areas may be relevant to Alzheimer disease and related disorders, but the overall impact of any changes requires adaptation at the top of the administrative structures in academia and funding agencies to support and encourage cooperative efforts among faculty investigators.

Fuller AD, Van Eldik LJ. · Department of Cell and Molecular Biology, Center for Drug Discovery and Chemical Biology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60611, USA. · J Neuroimmune Pharmacol. · Pubmed #18670887 No free full text.

Abstract: Phagocytosis is an essential mechanism for clearance of pathogens, dying cells, and other unwanted debris in order to maintain tissue health in the body. Macrophages execute this process in the peripheral immune system but in the brain microglia act as resident macrophages to accomplish this function. In the peripheral immune system, macrophages secrete Milk Fat Globule Factor-E8 (MFG-E8) that recognizes phosphatidylserine "eat me" signals expressed on the surface of apoptotic cells. MFG-E8 then acts as a tether to attach the apoptotic cell to the macrophage and trigger a signaling cascade that stimulates the phagocyte development, allowing the macrophage to engulf the dying cell. When this process becomes disrupted, inflammation and autoimmunity can result. MFG-E8 resides in the brain as well as in the periphery, and microglia express MFG-E8. However, the function of MFG-E8 in the brain has not been elucidated. We measured MFG-E8 production in the BV-2 microglial cell line and the role of this protein in the recognition and engulfment of apoptotic SY5Y neuroblastoma cells. BV-2 cells produced and released MFG-E8, which apoptotic SY5Y cells and the chemokine fractalkine further stimulated. Furthermore, MFG-E8 increased phagocytosis of apoptotic SY5Y cells, and a dominant negative form of MFG-E8 inhibited phagocytosis by BV-2 cells. Finally, brain MFG-E8 levels were altered in a mouse model of Alzheimer's disease. Our data suggest that MFG-E8 acts in the brain via microglia to aid in clearance of apoptotic neurons, and we hypothesize that a dysregulation of this process may be involved in neurodegenerative disease.

Munoz L, Ranaivo HR, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM. · Center for Drug Discovery and Chemical Biology, Northwestern University, 303 E Chicago Ave, Mailcode W896, Chicago, IL 60611, USA. · J Neuroinflammation. · Pubmed #17784957 links to  free full text

Abstract: BACKGROUND: An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38 alpha MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (A beta) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38 alpha MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes. METHODS: A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model. RESULTS: A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38 alpha MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits. CONCLUSION: The p38 alpha MAPK pathway is quantitatively important in the A beta-induced production of proinflammatory cytokines in hippocampus, and brain p38 alpha MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.

Hu W, Ranaivo HR, Roy SM, Behanna HA, Wing LK, Munoz L, Guo L, Van Eldik LJ, Watterson DM. · Center for Drug Discovery and Chemical Biology, Northwestern University, 303 E. Chicago Avenue, Mail Code W896, Chicago, IL 60611, USA. · Bioorg Med Chem Lett. · Pubmed #17079143 links to  free full text

Abstract: We report the development of a novel, aqueous-soluble, safe, small molecule, experimental therapeutic that suppresses injury-induced, proinflammatory cytokine increases in the brain, with resultant attenuation of synaptic protein biomarker loss and improvement in hippocampus-dependent behavioral deficits. A GMP production scheme for the active pharmaceutical ingredient, compound 17, is presented. The development and large-scale availability of this novel compound allow exploration of new, potentially disease-modifying, therapeutic approaches to CNS disorders.

Hu W, Ralay Ranaivo H, Craft JM, Van Eldik LJ, Watterson DM. · Center for Drug Discovery and Chemical Biology, Northwestern University Chicago, IL 60611, USA. · Curr Alzheimer Res. · Pubmed #15974919 No free full text.

Abstract: The neuroinflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to altering Alzheimer's disease (AD) progression. However, the efficacy and toxicological profile of compounds that focus only on classical NSAID targets have been disappointing to date. Therefore, we recently initiated an unbiased, integrative chemical biology approach that used a hierarchal set of cell-based screens, followed by efficacy analysis in a new AD-relevant animal model that more closely resembles human pathology endpoints in terms of neuroinflammation and neuronal loss. The prior investigations provided a proof of concept that targeting the neuroinflammation cycle may be a viable drug discovery approach for AD. However, recent informatics analyses of the high attrition rate in drug development have identified the need for starting drug development with lead compounds that are well below cut off values in computed molecular properties in order to facilitate late stage medicinal chemistry refinement to improve in vivo functions. We describe here how we are leveraging our novel, unbiased, integrative chemical biology approach for the rapid discovery of potential lead compounds for AD drug discovery. Specifically, we show that orally bioavailable compounds with the desired physical properties and in vivo functions can be identified in focused synthetic libraries composed of chemical diversifications of the inactive but privileged pyridazine molecular fragment.

White JA, Manelli AM, Holmberg KH, Van Eldik LJ, Ladu MJ. · Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA. · Neurobiol Dis. · Pubmed #15755672 No free full text.

Abstract: Activated glia, as a result of chronic inflammation, are associated with amyloid-beta peptide (Abeta) deposits in the brain of Alzheimer's disease (AD) patients. In vitro, glia are activated by Abeta inducing secretion of pro-inflammatory molecules. Recent studies have focused on soluble oligomers (or protofibrils) of Abeta as the toxic species in AD. In the present study, using rat astrocyte cultures, oligomeric Abeta induced initial high levels of IL-1beta decreasing over time and, in contrast, fibrillar Abeta increased IL-1beta levels over time. In addition, oligomeric Abeta, but not fibrillar Abeta, induced high levels of iNOS, NO, and TNF-alpha. Our results suggest that oligomers induced a profound, early inflammatory response, whereas fibrillar Abeta showed less increase of pro-inflammatory molecules, consistent with a more chronic form of inflammation.

Liu L, Li Y, Van Eldik LJ, Griffin WS, Barger SW. · Department of Geriatrics, University of Arkansas for Medical Sciences, 629 Jack Stephens Drive #807, Little Rock, AR 72205, USA. · J Neurochem. · Pubmed #15659225 No free full text.

Abstract: Both the astrocytic cytokine S100B and the pro-inflammatory interleukin-1 (IL-1) are elevated in Alzheimer's disease, and each has been implicated in Alzheimer-related neuropathology. We examined the gene-regulatory events through which S100B induces IL-1beta expression. In primary microglia, S100B activated the transcription factors Sp1 and NFkappaB, followed by an increase in IL-1beta mRNA levels. The latter was blocked by a peptide inhibitor of NFkappaB or by a double-stranded oligonucleotide containing a NFkappaB-binding site to serve as "decoy" DNA and reduce available NFkappaB. But in primary cortical neurons, decoy and siRNA experiments indicated that the IL-1beta induction by S100B was mediated by Sp1 without evidence of a role for NFkappaB. Our results suggest that the elevation of S100B and IL-1 in Alzheimer brain and consequent neurodegenerative events are mediated through cell-type specific gene-regulatory events, providing mechanistic insight into connections between glial activation and neuronal dysfunction.

Craft JM, Watterson DM, Frautschy SA, Van Eldik LJ. · Drug Discovery Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Neurobiol Aging. · Pubmed #15465624 No free full text.

Abstract: The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (Abeta)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human Abeta1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress Abeta-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

Craft JM, Van Eldik LJ, Zasadzki M, Hu W, Watterson DM. · Drug Discovery Program, Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · J Mol Neurosci. · Pubmed #15314259 No free full text.

Abstract: The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer's disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates beta-amyloid (Abeta)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Abeta-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of human Abeta1-42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.

Guo L, LaDu MJ, Van Eldik LJ. · Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · J Mol Neurosci. · Pubmed #15181248 No free full text.

Abstract: Chronically activated glia associated with amyloid plaques might contribute to neuronal dysfunction in Alzheimer's disease (AD) through generation of neuroinflammatory molecules. Apolipoprotein E (apoE), also found associated with amyloid plaques, has been hypothesized to serve an anti-inflammatory role in the CNS through its ability to modulate beta-amyloid (Abeta)-induced glial activation. To further characterize the effect of apoE on inflammation, we examined the ability of exogenously added human apoE3 and apoE4 to modulate neuro inflammatory responses of cultured rat glia. Apolipoprotein E3 (apoE3) and apoE4 suppressed oligomeric Abeta-induced production of inducible nitric oxide synthase and cyclo-oxygenase-2, supporting an anti- inflammatory role for apoE. Exogenous apoE also inhibited Abeta-induced production of endogenous apoE. However, exogenous apoE in the absence of Abeta stimulated production of the pro-inflammatory cytokine interleukin-1beta in an isoform-dependent manner, with apoE4 inducing a significantly greater response than apoE3. These data support the idea that Abeta stimulation of glial apoE limits neuroinflammation but that overproduction of apoE by activated glia might exacerbate inflammation. In addition, the observation that apoE4 has more robust pro-inflammatory activity than apoE3 provides a mechanistic link between the APOE4 allele and AD, and suggests potential apoE-based therapeutic strategies.

Watterson DM, Velentza AV, Zasadzki M, Craft JM, Haiech J, Van Eldik LJ. · Drug Discovery Program and Department of Molecular Pharmacology, Northwestern University Medical School, Chicago IL 60611, USA. · J Mol Neurosci. · Pubmed #14501026 No free full text.

Abstract: A prevailing hypothesis in Alzheimer's disease (AD) research is that chronically activated glia may contribute to neuronal dysfunction, through generation of a detrimental state of neuroinflammation. This raises the possibility in drug discovery research of targeting the cycle of untoward glial activation and neuronal dysfunction that characterizes neuroinflammation. Success over the past century with effective anti-inflammatory drug development, in which the molecular targets are intracellular enzymes involved in signal transduction events and cellular homeostasis, demands that a similar approach be tried with neuroinflammation. Suggestive clinical correlations between inflammation markers and AD contribute to the urgency in addressing the hypothesis that targeting selective glial activation processes might be a therapeutic approach complementary to existing drugs and discovery efforts. An academic collaboratorium initiated a rapid inhibitor discovery effort 2 yr ago, focused on development of novel compounds with new mechanisms of action in AD-relevant cellular processes, in order to obtain the small-molecule compounds required to address the neuroinflammation hypothesis and provide a proof of concept for future medicinal chemistry efforts. We summarize here our progress toward this goal in which novel pyridazine-based inhibitors of gene-regulating protein kinases have been discovered. Feasibility studies indicate their potential utility in current medicinal chemistry efforts focused on improvement in molecular properties and the longer term targeting of AD-related pathogenic processes.

Lam AG, Koppal T, Akama KT, Guo L, Craft JM, Samy B, Schavocky JP, Watterson DM, Van Eldik LJ. · Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA. · Neurobiol Aging. · Pubmed #11705636 No free full text.

Abstract: Compelling evidence links chronic activation of glia and the subsequent cycle of neuroinflammation and neuronal dysfunction to the progression of neurodegeneration in disorders such as Alzheimer's disease (AD). S100B, a glial-derived cytokine, is significantly elevated in the brains of AD patients and high concentrations of S100B are believed to be detrimental to brain function. As a first step toward elucidating the mechanisms by which S100B might be serving this detrimental role, we examined the mechanisms by which S100B stimulates glial inducible nitric oxide synthase (iNOS), an oxidative stress related enzyme that has been linked to neuropathology through the production of neurotoxic peroxynitrite. We report here that S100B stimulates iNOS in rat primary cortical astrocytes through a signal transduction pathway that involves activation of the transcription factor NFkappaB. NFkappaB activation was demonstrated by nuclear translocation of the p65 NFkappaB subunit, stimulation of NFkappaB-specific DNA binding activity, and stimulation of NFkappaB-dependent transcriptional activity. Furthermore, S100B-induced iNOS promoter activation was inhibited upon mutation of the NFkappaB response element in the promoter, and transfection of cells with an NFkappaB inhibitor blocked S100B-induced iNOS promoter activation and nitric oxide production. These studies define a signal transduction pathway by which S100B activation of glia could participate in the generation of oxidative stress in the brain.

Peskind ER, Griffin WS, Akama KT, Raskind MA, Van Eldik LJ. · Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98108, USA. · Neurochem Int. · Pubmed #11578776 No free full text.

Abstract: Postmortem demonstration of increased expression of biologically active S100B in Alzheimer's disease (AD) and its relation to progression of neuropathological changes across the cortical regions suggests involvement of this astrocytic cytokine in the pathophysiology of AD. The hypothesis that the overexpression of S100B in Alzheimer brain is related to the progression of clinical symptoms was addressed in living persons by measuring S100B concentrations in cerebrospinal fluid (CSF) from AD patients with a broad range of clinical dementia severity and from healthy older persons. The effect of normal aging on CSF S100B concentrations also was estimated. CSF S100B did not differ between all 68 AD subjects (0.98+/-0.09 ng/ml (mean+/-S.E.M.)) and 25 healthy older subjects (0.81+/-0.13 ng/ml). When AD subjects were divided into mild/moderate stage and advanced stage clinical dementia severity by the established Clinical Dementia Rating Scale (CDR) criteria, S100B was significantly higher in the 46 mild/moderate stage AD subjects (1.17+/-0.11 ng/ml) than in either the 22 advanced stage AD subjects (0.60+/-0.12 ng/ml) or the healthy older subjects. Consistent with higher CSF S100B in mild to moderate AD, there was a significant correlation among all AD subjects between CSF S100B and cognitive status as measured by the Mini Mental State Exam (MMSE) score. CSF S100B did not differ between healthy older subjects and healthy young subjects. These results suggest increased CNS expression of S100B in the earlier stages of AD, and are consistent with a role for S100B in the initiation and/or facilitation of neuritic plaque formation in AD brain.

Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, Mrak RE, Griffin WS. · The Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA. · Neurochem Int. · Pubmed #11578769 No free full text.

Abstract: Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylation of tau, a major component of the neurofibrillary tangles in Alzheimer's disease. This, together with findings showing that IL-1 activates MAPK-p38 in vitro and is markedly overexpressed in Alzheimer brain, suggest a role for IL-1-induced MAPK-p38 activation in the genesis of neurofibrillary pathology in Alzheimer's disease. We found frequent colocalization of hyperphosphorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain, and frequent association of these structures with activated microglia overexpressing IL-1. Tissue levels of IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isoforms of tau were elevated in these brains. Significant correlations were found between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and between the numbers of activated microglia overexpressing IL-1 and the numbers of both AT8- and MAPK-p38-immunoreactive neurons. Furthermore, rats bearing IL-1-impregnated pellets showed a six- to seven-fold increase in the levels of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (P<0.0001). These results suggest that microglial activation and IL-1 overexpression are part of a feedback cascade in which MAPK-p38 overexpression and activation leads to tau hyperphosphorylation and neurofibrillary pathology in Alzheimer's disease.