ブレインバンク死後脳を用いた神経生物学的研究
Neurobiological Study of Postmortem Brain from Brain Bank
S3-5-3-1
脳疾患研究とブレインバンク
Brain disease researches and brain bank

○岡澤均1
○Hitoshi Okazawa1
東京医科歯科大学神経病理学1
Dept Neuropathol, Tokyo Medical and Dental University1

In order to understand molecular pathologies of brain diseases, it is essential to analyze quantitative change of protein amounts and protein modifications. Especially, such quantitative analyses are the most important process to prove pathological hypotheses for various brain disorders. However, protein amount and protein modification are affected by protein degradation or additional protein modification that occur after death, and we do not know exactly how much and how fast such postmortem changes progress. We performed recently quantitative whole proteome analysis with mouse brains kept at 25 or 4 degree from 0 to 72 hours. Unexpectedly, we observed that most phosphoproteins were dramatically changed (0.1~3 folds), in time, temperature and protein species dependent manner (PLoS ONE 6(6): e21405, 2011). From this unexpected result, it is clear that quality control of brain bank critically affects protein researches of brain disease. I would like to stress the importance to discuss about how to build up a lucent and controlled brain bank from the aspect of storing conditions.
S3-5-3-2
小脳変性疾患研究の立場から
For the study of cerebllar degeneration

○石川欽也1, 佐藤望2, 尾崎心1, 初田裕幸2, 村山繁雄2, 水澤英洋1
○Kinya Ishikawa1, Nozomu Sato1, Kokoro Ozaki1, Hiroyuki Hatsuta2, Shigeo Murayama2, Hidehiro Mizusawa1
東京医科歯科大学脳神経病態学分野1, 東京都健康長寿医療センター高齢者ブレインバンク2
Dept. of Neurology and Neurosciences, Tokyo Medical and Dental University1, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology2

"The cerebellum is one of the several regions of the human brain that shows shrinkage by normal aging processes. However, there are not many histological changes as a result of aging as compared to the cerebrum in which we often see various remarkable changes such as senile plaques and neurofibrillary tangles. This may indicate that the ageing in the cerebellum is distinct from that in the cerebrum. Taking an advantage of brain bank resource, we undertook mRNA expression analysis in the cerebellum using microarray to clarify the gene expression changes as a consequence of aging. We found gene sets that are consistently altered in highly aged human cerebellum. Some of these may be involved in maintaining normal cerebellar aging. Similarly, we investigated mRNA expressions in the cerebellum of normally aged individuals and those affected cerebellar degenerations. Some genes which showed decreased expressions in degenerated cerebella are already known to be the cause of other inherited ataxias. This may indicate that there are some common molecular cascades underlying several distinct neurodegenerative diseases of the cerebellum."
S3-5-3-3
大脳変性疾患研究の立場から
For the study of human cerebral neurodegeneration

○富田泰輔1
○Taisuke Tomita1
東京大学大学院薬学系研究科 臨床薬学教室1
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo1

Several cerebral neurodegenerative diseases are characterized by abnormal deposition of protein aggregation together with massive neuronal loss; amyloid-beta and tau proteins in Alzheimer disease (AD), alpha-synuclein in Dementia with Lewy bodies (DLB), tau and TDP-43 in Frontotemporal Dementia (FTD). These deposited proteins were identified by biochemical as well as histopathological analyses of brains from patients. Intriguingly, genetic studies have now shown that mutations in genes encoding these aggregable proteins are linked to familial form of the diseases, suggesting that aggregation and deposition of these proteins are highly correlated to the pathogenesis of neurodegeneration. Moreover, biomarker studies in human subjects have suggested that molecules related to these deposited proteins could reflect the progression of the neurodegeneration and be useful for diagnosis for these diseases. Thus, pathological analysis of brains of patients would shed light into the molecular evidence of the etiology of neurodegeneration, and provide a novel approach for development of therapeutics as well as diagnostics. In this regard, brain bank network is critical for the study of cerebral neurodegenerative diseases, such as AD, DLB and FTD.
S3-5-3-4
脊髄疾患研究の立場から
For the study of spinal disorders

○勝野雅央1
○Masahisa Katsuno1
名古屋大院・医・神経内科1
Dept Neurol, Nagoya Univ, Nagoya1

The motor system consists of corticospinal upper motor neurons, lower motor neurons, neuromuscular junctions, and skeletal muscle. Impairment of this system results in various motor phenotypes including muscle atrophy, weakness, and spasticity. Amyotrophic lateral sclerosis (ALS) and spinal and bulbar atrophy (SBMA) are late-onset neurodegenerative disorders that affect motor neurons. Basic studies using cellular and animal models suggest that the pathogenesis of these motor neuron diseases share several pathological mechanisms such as the disruption of TGF-beta signaling and calcitonin gene-related peptide 1 (CGRP1)-JNK pathway. These hypotheses have been verified by analyses using autopsied human nervous tissues that reflect the end-stage pathological changes of motor neuron diseases. SBMA exclusively affects adult males, whereas females homozygous for the AR mutation do not manifest neurological symptoms. Pre-clinical studies using animal models show that the pathogenic AR-mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in clinical trials. Of note is the observation that the frequency of the pathogenic AR-bearing neurons in the anterior horn and brainstem of an autopsied patient, who underwent androgen deprivation for 2 years, was less than in non-treated SBMA patients. These findings strongly indicate that histopathological and biochemical analyses of autopsied brain are indispensable to the elucidation of pathogenesis and the development therapies for motor neuron diseases. However, these studies may encounter several challenges including post-mortem effects that mask disease-related molecular changes. An extensive loss of motor neurons from the affected region of brain and spinal cord may also hinder the analysis of remaining motor neurons in human. The validation of post-mortem samples is thus necessary for the successful research of human pathogenesis.
S3-5-3-5
高齢者ブレインバンクを用いたレビー小体病理の全身伝搬解析
Study of systemic propagation of Lewy body pathology - Brain Bank for Aging Research Project

○村山繁雄1
○Shigeo Murayama1
東京都健康長寿医療センター 高齢者ブレインバンク1
Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology1

Lewy body (LB) pathology is hypothesized to spread through neuronal network like prion. Braak proposed dual hit hypothesis that the pathogen of Parkinson disease (PD) comes from outside and initial seeding of LBAS starts from digestive tract to medulla oblongata or nasal cavity to olfactory bulb. We tried to study systemic propagation pattern of Lewy body (LB) pathology in human aging process. We recruited consecutive autopsy cases from our hospital for systemic screening and tissue banking to study LB pathology in October 2008. Until March 2012, 205 (69.5%) among the 295 consecutive autopsy cases were registered to our brain bank, including 129 males and 76 females. The mean age was 82.0 (SD 9.2) years and mean postmortem interval was 14 hours and 46 minutes. The areas selected for the screening followed the third DLB Consensus Guidelines, adding olfactory bulbs and thoracic spinal cords for CNS and olfactory epithelium, thoracic autonomic ganglia, adrenal glands, gastro- esophageal junctions, anterior walls of the left ventricle of the heart and skins for peripheral nervous system. Formalin- fixed, paraffin- embedded sections were immunohistochemically stained with anti- phosphorylated alpha- synuclein as well as tau, Abeta and TDP43 antibodies. Severity of LB pathology in the areas examined was graded 0-4, following the Consensus Guideline. Seventy five of the 205 cases (36.6%) contained LB pathology in at least one of the examined areas, including 17 cases (22.7%) of Parkinson disease or dementia with Lewy bodeies (DLB). The most frequent sites of LB pathology were olfactory bulb and amygdala, followed by locus ceruleus, dorsal motor nucleus of vagus and thoracic autonomic ganglia. Cases without LB pathology in PNS always contained LBAS in olfactory bulbs and vice versa. Our data may support Braak's dual hit hypothesis, but highlight the importance of peripheral sympathetic nervous system as the spot of initial seeding of LB pathology.

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