权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Establishment of Alzheimer model cell system and its application to therapeutics

阿尔茨海默病模型细胞系统的建立及其在治疗中的应用

基本信息

批准号：
07557332
负责人：
YOSHIKAWA Kazuaki
金额：
$ 0.96万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Alzheimer's disease (AD) is characterized by the progressive dementia as a result of massive neuronal death in the brain. Clarification of the pathogenesis of this disease is one of the most urgent medical problems. Amyloid beta protein (Abeta) is the principal component of amyloid fibrils that are deposited in the brain affected by AD.Thus Abeta might be closely associated with the pathogenesis of the disease. Abeta is derived from the precursor, termed the amyloid precursor protein (APP). In an attempt to elucidate the pathological implications of intracellular accumulation of APP in postmitotic neurons, we transferred APP cDNA into rat hippocampal neurons under cultured conditions by using a replication-defective adenovirus vector. Neurons accumulating the membrane-bound form of APP showed greater responsiveness to exogenous glutamate than non-expressing control neurons, suggesting that elevated calcium levels potentially cause neurodegeneration. Moreover, we demonstrated that overexpression of APP by the same APP-expressing adenovirus vector induces death of human cultured neurons derived from human embryonal carcinoma cells within several days. When an APP-expressing adenovirus wazs injected into a rat hippocampus, some of the infected neurons in the hippocampal formation underwent severe degeneration displaying shrunk perikarya along with synaptic abnormalities in a few days. These experimental systems enable us to study detailed molecular mechanisms of APP-induced neurodegeneration, and will be useful for studies on pathogenesis of AD and development of therapeutics.

阿尔茨海默病 (AD) 的特点是由于大脑中大量神经元死亡而导致进行性痴呆。阐明该病的发病机制是当前最紧迫的医学问题之一。淀粉样β蛋白(Abeta)是沉积在受AD影响的大脑中的淀粉样原纤维的主要成分。因此Abeta可能与该疾病的发病机制密切相关。 Abeta 源自前体，称为淀粉样前体蛋白 (APP)。为了阐明有丝分裂后神经元细胞内 APP 积累的病理学意义，我们使用复制缺陷型腺病毒载体在培养条件下将 APP cDNA 转移到大鼠海马神经元中。与不表达的对照神经元相比，积累膜结合形式 APP 的神经元对外源性谷氨酸的反应性更强，这表明钙水平升高可能导致神经变性。此外，我们证明，通过相同的表达 APP 的腺病毒载体过度表达 APP 会在几天内诱导源自人胚胎癌细胞的人培养神经元死亡。当将表达 APP 的腺病毒注射到大鼠海马体中时，海马结构中的一些受感染神经元在几天内发生严重变性，表现出核周萎缩和突触异常。这些实验系统使我们能够研究 APP 诱导的神经变性的详细分子机制，并将有助于研究 AD 的发病机制和治疗方法的开发。