QUANTITATIVE INDICES OF NEURON VULNERABILITY IN DEMENTIA

痴呆症中神经元脆弱性的定量指数

• 批准号: 6446894
• 负责人: PATRICK R HOF
• 金额: $ 19.62万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6446894
• 关键词: AMPA receptors; Alzheimer's disease; Macaca fascicularis; NMDA receptors; confocal scanning microscopy; dementia; fluorescence microscopy; frontal lobe /cortex; glutamate receptor; human tissue; immunocytochemistry; neocortex; neural degeneration; neurochemistry; neurofibrillary tangles; neurofilament; neurofilament proteins; neuropathology; pathologic process; prefrontal lobe /cortex; pyramidal cells; receptor expression

Alzheimer's disease (AD) is characterized by extensive neuronal death in the cerebral cortex. This loss of neurons is correlated with the severe functional decline in cognition and memory observed in AD patients. Neuropathological changes restricted to the hippocampal formation are a consistent reflection of age-related memory impairment, but overt dementia is present only in cases with neocortical involvement. Distinct subpopulations of neocortical neurons undergo severe degeneration in AD, while others are remarkably preserved even at late stages of the disease. Thus, in association neocortical areas a subset of pyramidal neurons are particularly vulnerable in AD, while other neuron classes remain viable throughout the progression of AD. The vulnerable neurons are all characterized by their large size, their extensive dendritic arborization and their relatively high content of neurofilament protein. Further investigations have demonstrated that these neurons are also involved in neurofibrillary tangle (NFT) formation and that there exist age-related shifts in the expression of neurofilament protein and other molecules, such as glutamate receptor subunit proteins (GluRs), that may render a neuron prone to neurodegeneration. However, the degree to which molecular and morphological alterations restricted to identifiable neuronal populations represent reliable thresholds reflecting early degeneration or functional deficits has not yet been determined. This component is designed to analyze quantitatively the molecular and morphologic correlates or functional decline and the progression of neuronal alterations in the superior frontal cortex of AD cases by developing quantitative indices of neurofibrillary degeneration (INDs) based on ratios of stereologic estimates of neurons and NFTs in the superior frontal cortex. We will also determine quantitatively the complement of GluRs in identified sets of corticocortical projections linking the prefrontal cortex to temporal and parietal association areas in the macaque monkey to test the hypothesis that substantial differences exist in the distribution of key GluRs among the neurons of origin of these projections. Based on this prediction, we will investigate whether the neurons at risk in AD exhibit overall low staining intensity for the AMPA subunit GluR2 and that progressive shifts in AMPA and NMDA subunits expression will take place as neurons undergo degenerative changes. We hypothesize that a decrease in GluR2 staining intensity will be concomitant of the appearance of the earliest degenerative neuronal changes in AD, in a selected population of neurons, but that no such association will be observed with NMDAR1. The detailed quantitative data obtained from these studies will provide crucial information on the anatomic and neurochemical determinants of selective neuronal vulnerability in AD.

阿尔茨海默氏病（AD）的特征是广泛的神经元死亡 大脑皮层。神经元的这种丧失与严重的 AD患者观察到的认知和记忆力下降。 限于海马形成的神经病理学变化是 与年龄相关的记忆障碍的一致反射，但公开 痴呆仅在新皮质受累的情况下存在。清楚的 新皮质神经元的亚群会在AD中发生严重变性， 而其他人也被明显保存在 疾病。因此，在新皮质区域联合锥体子集 神经元在AD中特别容易受到伤害，而其他神经元课程 在AD的整个过程中保持可行。脆弱的神经元 都以它们的大小为特征，其广泛的树突状 树博化及其相对较高的神经丝蛋白含量。 进一步的研究表明，这些神经元也是 参与神经纤维缠结（NFT）形成，存在 与年龄相关的神经丝蛋白和其他表达的变化 分子，例如谷氨酸受体亚基蛋白（glurs），可能 使神经变性易发神经元。但是，在以上的程度 分子和形态变化限于可识别的 神经元人群代表可靠反映的可靠阈值 尚未确定退化或功能缺陷。这 组件旨在定量分析分子和 形态学相关或功能下降和进展 通过 开发神经原纤维变性（IND）的定量指数 基于神经元和NFT的立体估计值的比率 优质额叶皮层。我们还将定量确定 在确定的皮质皮质投影集中的gl胶的补充 将前额叶皮层连接到时间和顶叶协会区域 在猕猴中测试了实质性的假设 在神经元之间的关键胶的分布中存在差异 这些预测的起源。根据这个预测，我们将 调查AD中有风险的神经元是否表现出总体低 AMPA亚基Glur2的染色强度和该渐进性 AMPA和NMDA亚基表达的变化将作为神经元发生 发生退化性变化。我们假设glur2的减少 染色强度将是最早的外观 AD的退化性神经元变化，选定的人群 神经元，但是将与NMDAR1观察到任何这种关联。这 从这些研究获得的详细定量数据将提供 有关解剖学和神经化学决定因素的关键信息 AD中的选择性神经元脆弱性。