CORTICO-CORTICAL LOSS IN ALZHEIMERS DISEASE IN THE AGED

老年人阿尔茨海默病的皮质-皮质损失

• 批准号: 3117764
• 负责人: JOHN H MORRISON
• 金额: $ 19.42万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3117764
• 关键词: Alzheimer's disease; Macaca; acetylcholine; brain cell; brain stem; cell type; efferent nerve; gamma aminobutyrate; glutamates; hippocampus; histochemistry /cytochemistry; human tissue; immunochemistry; microtubule associated protein; monoclonal antibody; neocortex; neural degeneration; neurofibrillary tangles; neurofilament; neuronal transport; neurotransmitters; postmortem; pyramidal cells

The major neurodegenerative disorders display a high degree of selective vulnerability in regard to the distribution of pathologic lesions. This selective vulnerability is apparent in the disease-related profile of neuronal loss, and degeneration of specific pathways. For example, in Alzheimer's disease (AD), the distribution of pathologic profiles and cell loss suggest that the cells of origin and circuits that comprise certain parahippocampal projections and corticocortical circuits in neocortex are devastated in AD, whereas many other elements of cortical circuitry are resistant to pathology. Patterns of selective vulnerability in the neocortex offer important clues as to which cortical circuits are compromised in a given disease, but our ability to relate such patterns to potential cellular or molecular pathogenetic mechanisms is greatly hampered by our lack of data correlating biochemical phenotype with connectivity in the primate neocortex. This proposal is designed to provide such information on the corticocortical projections in the monkey. We have demonstrated that the pyramidal cells that furnish corticocortical projections are not homogeneous in regard to biochemical phenotype and/or morphology and thus, by our criteria do not represent a uniform cell type. We hypothesize that both the cytoskeletal and neurotransmitter profiles of these neurons will be a crucial characteristic of their biochemical phenotype and will relate systematically to their connectivity patterns. For example, specific corticocortically projecting neurons win be characterized as to their content of neurofilament and microtubule-associated proteins, as well as whether or not they use glutamate as a neurotransmitter, or contain receptors for glutamate, acetylcholine, or GABA and if so, the precise dendritic distribution of each receptor will be determined. In addition, die precise distribution of chemically identified afferents to corticocorically projecting neurons will be determined. Techniques that combine retrograde transport, immunohistochemistry and intracellular loading will be used to characterize several different classes of corticocortically projecting neurons. By considering location, connectivity (synaptic inputs and efferent target), morphology, and biochemical phenotype, subtypes of corticocortically projecting cells can be defined and their relative contribution to a given corticocortical projection can be determined. We predict that the comprehensive profile Of a given cell, and in turn, a given projection, will be strongly related to its role in normal cortical function and to its vulnerability in AD or other neurodegenerative disorders. If we can pinpoint the elements of the biochemical and anatomic phenotype that are most clearly linked to differential cellular vulnerability in AD, then we will be one step closer to developing means of protecting those neurons that degenerate in AD. The protection of these neurons must be the paramount goal in developing a strategy for the management of AD, since prevention of a neurodegenerative disease is much more likely to be achievable than the development of a cure.

主要的神经退行性疾病表现出高度的 关于病理分布的选择性脆弱性 病变。 这种选择性脆弱性在与疾病有关的 神经元丧失和特定途径的变性的特征。 为了 例如，在阿尔茨海默氏病（AD）中，病理学的分布 剖面和细胞损失表明原始细胞和电路的细胞 包括某些帕拉希峰预测和皮质皮层电路 在新皮层中，在AD中遭到破坏，而皮质的许多其他元素 电路对病理具有抵抗力。 选择性脆弱性的模式 在新皮层中，有关哪些皮质电路是重要的线索 在给定疾病中受到妥协，但我们将这种模式联系起来的能力 潜在的细胞或分子致病机制受到极大阻碍 由于我们缺乏将生化表型与连通性相关的数据 灵长类动物新皮层。 该建议旨在提供这样的 有关猴子皮质皮质预测的信息。 我们有 证明提供皮质皮质的金字塔细胞 关于生化表型和/或 形态学，因此，根据我们的标准，形态并不代表均匀的细胞类型。 我们假设均具有细胞骨架和神经递质的特征 这些神经元将是其生化的关键特征 表型，并将系统地与它们的连接模式联系起来。 例如，特定皮层预测神经元的胜利是 其含义的神经丝和 微管相关蛋白，以及它们是否使用 谷氨酸作为神经递质，或含有谷氨酸的受体， 乙酰胆碱或GABA，如果是的，则是确切的树突状分布 每个受体将被确定。 此外，死亡精确分布 化学鉴定的传入corticocortiontipocorthins fothing神经元 将确定。 结合逆行运输的技术， 免疫组织化学和细胞内负荷将用于表征 几个不同类别的皮层投射神经元。 经过 考虑位置，连通性（突触输入和传出目标）， 形态学和生化表型，皮层皮质的亚型 可以定义投影细胞，并对给定的相对贡献 可以确定皮质皮质投影。 我们预测 给定单元的全面概况，然后给定投影， 将与其在正常皮质功能中的作用密切相关 AD或其他神经退行性疾病的脆弱性。 如果可以的话 查明生化和解剖表型的元素是 最清楚地与AD中的差分细胞脆弱性相关，然后我们 将更接近开发保护这些神经元的手段的一步 在AD中退化。 这些神经元的保护必须是 为了制定AD管理策略的最高目标，因为 预防神经退行性疾病更有可能是 比治愈的开发可以实现。