MOolecular mechanism of senile dementia. -summary of research-

我们研究了老年大脑神经退行性过程与阿尔茨海默病（AD）的分子机制。神经营养因子包括神经生长因子（NGF）及其家族如BDNF、NT-3、4、5及其受体（Trk、A、B、C）在分子和蛋白水平上进行了研究。介绍了利用特异性抗体检测这些物质的高灵敏度方法。克隆并发现了一种新的细胞粘附分子甘糖苷作为神经突生长因子。GIF是一种生长抑制因子，是一种金属硫蛋白样蛋白，在AD大脑中缺乏。AD的两种异常结构；老年斑和神经纤维缠结配对的herical filament （PHF）通过每个成分- β和tau蛋白进行分析。研究了这些蛋白的水解加工、修饰和代谢。1-42（43）残基的β蛋白主要存在于未成熟的弥漫性斑块中，而1-40存在于斑块核心和淀粉样血管病中。在高拷贝数培养的神经细胞中，β前体蛋白（APP）基因在APP毒性作用下死亡时间较早。phf主要由tau蛋白激酶（TPK） I和II诱导的异常磷酸化的tau蛋白组成。每个激酶分别是糖原合成酶激酶3 （GSK 3）和细胞周期蛋白依赖性激酶5 （cdk5）。我们的成员披露了神经细胞过程中运动分子的超微结构和功能分析。对第14、19和21号染色体进行了AD的分子遗传学研究。日本早发性家族性AD的基因位点疑似在14号染色体8cM长度内，最终与Sherrington等报道的早老素I （S182）基因对应。位于19号染色体上的载脂蛋白E （Apo E）基因E4异构体与家族性和散发性AD的晚、早发性相关。在一些日本家庭中也发现了21号染色体上APP基因密码子717点突变。最近，我们的成员Less报道了人类21号染色体整个长臂的I型限制性内切图

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