P3-179

Poster P3:: Tuesday Posters P3-178

DIFFUSE AND NEURITIC PLAQUES, NEUROFIBRILLARY TANGLES, AND APOE GENOTYPE IN PRECLINICAL AD

Catherine M. Roe, Chengjie Xiong, J. Philip Miller, John C. Morris, Washington University School of Medicine, St. Louis, MO, USA. Contact e-mail: [email protected] Background: A recent study indicated that, among individuals with autopsy-diagnosed AD, participants who were nondemented within one year prior to death were more likely to have frequent diffuse plaques on autopsy than frequent neuritic plaques, whereas demented participants were more likely to have frequent neuritic plaques than frequent diffuse plaques. Nondemented participants were further characterized by a greater likelihood of having frequent neurofibrillary tangles and at least one APOE e4 allele. Objectives: To further explore the respective roles of diffuse plaques, neuritic plaques, neurofibrillary tangles, and APOE genotype in preclinical dementia. Methods: Participants (aged 65⫹ years at death) meeting Khachaturian (N⫽1,009), Low, Intermediate, or High Likelihood for NIA/Reagan (N⫽1,704), or Possible, Probable, or Definite CERAD (N⫽1,835) neuropathological criteria for AD with data in the National Alzheimer’s Coordinating Center Minimum (MDS) and Neuropathology (NDS) Data Sets made up the study samples. In generalized linear mixed models (using the logit link function and adjusting for Alzheimer Disease Center effects) which included variables reflecting the frequency of neuritic plaques, diffuse plaques, and neurofibrillary tangle stage, tangles were associated with receiving a dementia diagnosis within one year of death in the three samples. Frequency of neuritic plaque pathology was related to receiving a dementia diagnosis within one year of death in samples defined using NIA/Reagan (F(2,1216)⫽6.72, p⫽.0013), CERAD (F(2,1187) ⫽6.92, p⫽.0010) and Khachaturian (F(2,676)⫽2.87, p⫽.0575) criteria. Dementia was not associated with frequency of diffuse plaques in any sample. Similar models using APOE genotype instead of the neuropathological variables indicated that APOE genotype also predicts dementia. APOE genotype is associated with the likelihood of having frequent tangles, and neuritic plaques, but not diffuse plaques, in each sample. Conclusions: Preliminary data suggest that a premorbid diagnosis of dementia among autopsy-diagnosed individuals with AD is associated with APOE genotype, and with degree of tangle and neuritic plaque, but not diffuse plaque, pathology. Diffuse plaques may, however, play an important role in AD development at earlier stages of the disease, in accordance with previous reports. More work is needed to determine whether relationships between neuropathology and dementia among individuals with preclinical AD can be explained by APOE genotype. P3-179

PROSTAGLANDIN E2 SYNTHESIS IS ASSOCIATED WITH ALZHEIMER’S DISEASE PATHOLOGY AND IS SUGGESTIVE OF PATHOGENIC POTENCY

Yoshiharu Akitake1, Daisuke Kamei2, Kazuyuki Machida1, Hiroyasu Akatsu3, Kenji Kosaka4, Kazuhiko Ono1, Manabu Nakashima1, Ichiro Kudo2, Mitsuo Takahashi1, 1Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; 2Showa University School of Pharmaceutical Sciences, Tokyo, Japan; 3Choju Medical Institue, Fukushimura Hospital, Toyohashi, Aichi, Japan; 4Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan. Contact e-mail: [email protected] Background: The main pathological features of senile plaques and neurofibrillary tangles in Alzheimer’s disease (AD) brains are associated with inflammatory processes such as activation of microglia and astrocytes, or activation of the complement system. The discovery of the inflammatory pathogenesis of AD has promoted anti-inflammatory strategies for treating AD patients. Several NSAIDs which have been used in clinical trials all have the ability to inhibit cyclooxygenase (COX). However, they have brought relatively severe adverse effects, because of the concomitant in-

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hibition of the synthesis of other prostanoids. Prostaglandin E2 (PGE2) is finally synthesized by PGE2 synthase (PGES) followed by COX. Objective: To clarify the relationship between the production of PGE2 and its contribution to AD pathology in autopsied brain samples. Method: We used a novel anti-membrane-bound PGES-1 (anti-mPGES-1) antibody for immunohistochemical examination. Autopsied brain samples from the Fukushimura Brain Bank included fixed brain tissues of AD patients, various disease control patients and physiologically aged persons. Results: When we examined the distribution of PGES in AD brain by immunohistochemistry, we found intense staining by anti-mPGES-1 antibody. This staining was strong solely in the hippocampus of the AD patients, and no differences were apparent between any of the AD and physiologically aged samples from other parts of the brain. Conclusion: mPGES-1 contributes to the synthesis of PGE2 chiefly triggered by inflammation, suggesting that the overexpression of mPGES-1 plays an active role in the deterioration of AD. Some reports have demonstrated that PGE2 is neurotoxic, while others describe it as neuroprotective. Therefore, in vitro experiments to clarify the real significance of suggestive PGE2 over-production associated with AD pathology should be carried out. P3-180

STRUCTURAL BASIS OF NORADRENERGIC SYSTEM’S ABILITY TO MODULATE HIPPOCAMPAL INHIBITORY CIRCUITS AND RESPOND TO ESTROGEN

Riitta A. Miettinen, University of Kuopio, Kuopio, Finland. Contact e-mail: [email protected] Estrogen’s improving effect on the performance of Alzheimer’s disease (AD) patients is supposed to be largely due to estrogen’s promoting action on the malfunctioning cholinergic system. However, the beneficial effect of estrogen on brain function can be mediated by other neurotransmitter systems as well. The present study reports that similarly to the cholinergic neurons in the basal forebrain the noradrenergic neurons in the locus coeruleus contain estrogen receptor-alfa thus indicating that also noradrenergic system is able to respond to estrogen. Furthermore, examination of the termination pattern of dopamine-beta-hydroxylase (DBH) containing fibers in the hippocampus revealed that similarly to cholinergic system also noradrenergic system takes part in modulating hippocampal inhibitory processes. The detailed light and electron microscopic analyses showed that DBH-positive fibers select among the target interneurons such that they form synaptic contacts with calretinin and somatostatin-containing interneurons, but never with the parvalbumin-containing cells. Nonpyramidal cells containing calbindin D28K receive only occasional input. These observations indicate that noradrenaline modulates hippocampal electrical activity via GABAergic interneurons that are known to participate in feedforward distal dendritic inhibition. A recent study by Rudick et al. (J.Neurosci, 2003) showed that cholinergic lesion attenuates estrogeninduced disinhibition in the hippocampus. However, the effect of cholinergic depletion was only partial suggesting that also other mechanisms contribute to estrogen-induced disinhibition in the hippocampus. The present observations provide strong evidence that the noradrenergic system can be an important contributor in this process. As recent studies have shown that the cholinergic and noradrenergic system interact also in neuroprotection and response of the nervous system to injury, these findings can open new venues for our understanding of AD pathology which includes loss of both cholinergic and noradrenergic neurons, and has high incidence specifically in elderly postmenopausal women suffering from diminished levels of estrogen. Considering that the degeneration of the cholinergic systems in AD results in learning and memory deficits, but loss of noradrenergic neurons induce severe behavioral and psychological symptoms that cause major burden for caregivers, further investigation of the role of the noradrenergic system and possible new intervention strategies in AD should be warranted.