PATHOLOGY IN ALZHEIMER'S DISEASE

某些海马神经元群体似乎比 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 CA1区、下丘脑和内嗅区的海马神经元 大脑皮层更容易发生细胞死亡，而 神经原纤维缠结和神经炎(老年性)斑块 齿状回和CA3区的神经元。主要目标 这项建议的目的是在尸检中使用原位杂交 人脑组织基因表达差异的研究 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本，它 在AD发病过程中可能存在差异调节。 初步研究表明，总淀粉样β蛋白mRNA 在下丘旁和内嗅觉皮质中水平升高 广告。我们假设β-淀粉样蛋白的差异表达- 蛋白mRNA在AD的发病机制中起作用，因此这些 研究旨在确定这种与AD相关的增加是否 在副下丘是由于表达了一种特殊的形式 淀粉样β蛋白mRNA的表达，其产物可能优先形成 淀粉样蛋白沉积在疾病中。 另一个要检验的假说是胆碱能神经元 在内侧隔区和斜角带复合体中 海马体基因产物。基底前脑胆碱能缺陷 功能，包括细胞萎缩和丧失，已被证明发生 在AD早期，可能会对Target产生病理后果 海马结构中的神经元群。神经生长 从海马体释放的因子似乎调节 衰老过程中基底前脑胆碱能神经元的完整性 过程中，神经生长因子受体分子提供了一个 监测隔-海马区完整性的良好标志物 用原位杂交和原位杂交检测途径 免疫细胞化学，在人类衰老的大鼠模型中， 行为受损的老年大鼠。后续研究将是 在人脑中进行，以确定是否存在类似的关系 神经生长因子受体的调节和 阿尔茨海默病的海马区病理及基因表达。

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.