MOolecular mechanism of senile dementia. -summary of research-

我们研究了老年脑和阿尔茨海默病(AD)神经退变过程的分子机制，从分子和蛋白质水平研究了神经营养因子，包括神经生长因子(NGF)及其家族BDNF、NT-3、4、5及其受体(Trk、A、B、C)。介绍了使用特定抗体检测这些物质的高灵敏方法。克隆并揭示了一种新的细胞黏附分子gicerin作为神经突起生长因子。GIF是一种生长抑制因子，是一种在AD脑中缺乏的金属硫蛋白样蛋白。通过Abeta和tau蛋白分析了AD的两种异常结构：老年斑和神经纤维缠绕的遗传丝(PHF)。对这些蛋白质的蛋白质降解、修饰和代谢进行了研究。Aβ蛋白1-42(43)残基主要存在于未成熟的弥漫性斑块中，1-40残基主要存在于斑块核心和淀粉样血管病变中。高拷贝数…培养的神经细胞Abeta前体蛋白(APP)基因主要由tau蛋白激酶(TPK)I和Tau蛋白II诱导的异常磷酸化的tau蛋白组成，分别是糖原合成酶3(GSK 3)和细胞周期蛋白依赖性蛋白5(CDK 5)。我们的成员揭示了神经细胞突起中运动分子的超微结构和功能分析，并对14、19和21号染色体进行了AD的分子遗传学研究。推测日本早发型家族性AD的基因座位于14号染色体，长度在8 cM以内，与Sherrington等报道的早老素I(S182)基因相对应。载脂蛋白E(Apo E)基因E4等位基因位于19号染色体上，与晚发性和早发性AD有关，不仅与日本家族性AD有关，而且与散发性AD有关。在少数日本家系中也发现了APP基因21号染色体717密码子的点突变。我们的成员Less最近报道了人类21号染色体整个长臂的Not I限制图

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 … More 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