Grant-in-Aid for Scientific Research on Priority Areas.
|Research Institution||KYUSHU UNIVERSITY|
TATEISHI Jun Kyushu University, Fac.of Medi., Professor, 医学部, 教授 (70033305)
山口 晴保 群馬大学, 医療技術短期大学, 教授 (00158114)
貫名 信行 東京大学, 医学部, 講師 (10134595)
石浦 章一 東京大学, 応用微生物研究所, 助教授 (10158743)
勝沼 信彦 徳島文理大学, 健康科学研究所, 所長 (50035375)
中村 重信 広島大学, 医学部, 教授 (30026843)
TAKAKU Fumimaro Int.Med.Center.of Japan President, 総長 (40048955)
IMAHORI Kazutomo Mitubishi Kase Inst.of Life Sci., Emiritus President, 名誉所長 (40012174)
TSUJI Syouji Niigata University, Dept.of Neurology, Professor, 脳研究所, 教授 (70150612)
IHARA Yasuo Tokyo University, Fac.of Med., Professor, 医学部, 教授 (60114386)
HATANAKA Hiroshi Osaka University, Inst.of Protein Res., Professor, 蛋白質研究所, 教授 (60208519)
|Project Fiscal Year
1992 – 1995
Completed(Fiscal Year 1995)
|Budget Amount *help
¥166,300,000 (Direct Cost : ¥166,300,000)
Fiscal Year 1995 : ¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1994 : ¥19,400,000 (Direct Cost : ¥19,400,000)
Fiscal Year 1993 : ¥92,200,000 (Direct Cost : ¥92,200,000)
Fiscal Year 1992 : ¥51,700,000 (Direct Cost : ¥51,700,000)
|Keywords||senile dementia / molecular mechanisms / Alzheimer's disease / neurotrophic factors / neuronal cell death / DNA diagnosis / gene analysis / 老年痴呆 / 分子機構 / アルツハイマー病 / 神経栄養因子 / 神経細胞死 / 遺伝子診断 / 遺伝子解析 / 細胞死 / ベータたんぱく / タウたんぱく / アポEたんぱく / 家族性アルツハイマー病 / 神経原線維変化 / PHF / タウ蛋白 / 老人斑 / Abeta蛋白 / β蛋白 / βアミロイド前駆蛋白|
We studied molecular mechanisms of neurodegenerative processes of aged brains and Alzheimer's disease (AD).
Neurotrophic factors including nerve growth-factor (NGF) and its families such as BDNF,NT-3,4,5 and their reseptors (Trk, A,B,C) were studied at molecular and protein levels. Highly sensitive methods to detect these substances using specific antibodies were introduced. A novel cell adhesion molecule, gicerin was cloned and disclosed to act as neurite outgrowth factor. A growth inhibitory factor, GIF is a metallothionein-like protein and deficient in AD brains.
Two abnormal structures in AD ; senile plaques and neuro-fibrrillary tangle-paired herical filaments (PHF) were analyzed through each constituents-Abeta and tau proteins. Proteolytic processing, modification and metabolism of these proteins were studied. Abeta protein with 1-42(43) residues exists mainly in inmature, diffuse plaques, while 1-40 in plaque cores and amyloid angiopathy. Cultured neural cells with high copy numbe
rs of Abeta precursor protein (APP) gene died earlier from toxicity of APP.
PHF is mainly composed of abnormally phosphorylated tau protein which is induced by tau protein kinase (TPK) I and II.Each kinase was disclosed to be a glycogen synthase kinase 3 (GSK 3) and cyclin-dependent kinase 5 (CDK 5), respectively. Ultrastructural and functional analyzes of motor molecules in nerve cell processes were disclosed by our members.
Molecular genetic studies on AD were done concerning chromosomes 14,19 and 21. Gene locus of the early onset familial AD in Japan was suspected within 8cM length in chromosome 14 which was finally corresponded to presenilin I (S182) gene reported by Sherrington et al. The E4 isofprm of apolipoprotein E (Apo E) which gene locates on chromosome 19 was related with late and early onset AD,not only of familial but sporadic patients in Japan. A point mutation at codon 717 of APP gene on chromosome 21 was also proved in a few Japanese families. A not I restriction map of the entire long arm of human chromosome 21 was lately reported by our members Less