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PATHOLOGY IN ALZHEIMER'S DISEASE

阿尔茨海默病的病理学

基本信息

批准号：
3477624
负责人：
GERALD A HIGGINS
金额：
$ 9.14万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 1990-11-30
项目状态：
已结题

项目摘要

Certain hippocampal neuronal populations appear to be more vulnerable than other to the pathological consequences of Alzheimer's disease (AD). Neuropathological studies have shown that hippocampal neurons of the CA1 field, subiculum and entorhinal cortex are more prone to cell death, and the development of neurofibrillary tangles and neuritic (senile) plaques, than are neurons in the dentate gyrus and CA3 field. The major objective of this proposal is to use in situ hybridization in postmortem human brain tissue to study differences in gene expression between these cell populations, with particular regard to the expression of alternate transcripts of the amyloid-beta-protein gene, which may be differentially regulated during the course of AD. Preliminary studies suggest that total amyloid-beta-protein mRNA levels are elevated in the parasubiculum and entorhinal cortex in AD. We hypothesize that differential expression of amyloid-beta- protein mRNA plays a role in pathogenesis of AD, and thus these studies are designed to determine whether this AD-related increase in the parasubiculum is due to the expression of a particular form of amyloid-beta-protein mRNA, whose product may preferentially form amyloid deposits in the disease. Another hypothesis that will be tested is that cholinergic neurons in the medial septum and diagonal band complex contribute to hippocample gene products. Deficits in basal forebrain cholinergic function, including cell atrophy and loss, have been shown to occur early in AD, and may have pathological consequences for target neuronal populations in the hippocampal formation. Nerve growth factor, released from the hippocampus, appears to regulate the integrity of basal forebrain cholinergic neurons during the aging process, and the nerve growth factor receptor molecule provides a good marker for monitoring the integrity of the septo-hippocampal pathway examined using in situ hybridization and immunocytochemistry, in a rat model of human aging, the behaviorally-impaired aged rat. Subsequent studies will be undertaken in human brain, to determine if a similar relationship exists between nerve growth factor receptor regulation and hippocampal pathology and gene expression in AD.

某些海马神经元群体似乎比其他神经元群体更多。比其他人更容易受到阿尔茨海默病（AD）。神经病理学研究表明海马CA 1区、下托和内嗅区的神经元皮质更容易发生细胞死亡，神经纤维缠结和神经炎（老年）斑块，齿状回和CA 3区的神经元。主要目的这项提议的一个重要目的是利用原位杂交技术人类大脑组织研究基因表达的差异，这些细胞群体，特别是关于表达淀粉样β蛋白基因的交替转录，可能在AD的病程中受到不同的调节。初步研究表明，总淀粉样β蛋白mRNA 水平升高，在subiculum和内嗅皮层， AD. 我们假设淀粉样β蛋白的差异表达，蛋白质mRNA在AD的发病机制中起作用，因此这些研究旨在确定这种AD相关的增加是否是由于表达了一种特殊的形式 β-淀粉样蛋白mRNA，其产物可能优先形成淀粉样蛋白沉积另一个将被验证的假设是胆碱能神经元在内侧隔和斜角带复合体有助于多基因产物。基底前脑胆碱能神经缺陷功能，包括细胞萎缩和损失，已被证明会发生早期AD，并可能对靶向海马结构中的神经元群体。神经生长从海马体释放的因子，似乎可以调节基底前脑胆碱能神经元老化过程中的完整性过程，神经生长因子受体分子提供了一个是监测隔-海马完整性的良好标记物使用原位杂交检查途径，免疫细胞化学，在人类衰老的大鼠模型，行为受损的老年大鼠后续研究将在人脑中进行，以确定是否有类似的关系，存在于神经生长因子受体调节和 AD患者海马病理及基因表达