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疾病相关的疾病中很明显 神经元损失和特定通路退化的概况。 为了 例如，在阿尔茨海默病 (AD) 中，病理学分布 概况和细胞损失表明，细胞的起源和电路 包括某些海马旁投射和皮质回路 新皮质中的许多元素在 AD 中遭到破坏，而皮质中的许多其他元素 电路对病理具有抵抗力。 选择性脆弱性的模式 新皮质中的区域提供了关于哪些皮质回路是的重要线索 在特定疾病中受到损害，但我们将这些模式与 潜在的细胞或分子发病机制受到极大阻碍 由于我们缺乏将生化表型与连接性相关联的数据 灵长类新皮质。 该提案旨在提供这样的 有关猴子皮质投射的信息。 我们有 证明提供皮质皮质的锥体细胞 在生化表型和/或方面的预测并不均匀 因此，根据我们的标准，形态并不代表统一的细胞类型。 我们假设细胞骨架和神经递质特征 这些神经元将是其生化的一个重要特征 表型并将系统地与其连接模式相关。 例如，特定的皮质投射神经元将被 表征其神经丝的含量和 微管相关蛋白，以及它们是否使用 谷氨酸作为神经递质，或含有谷氨酸受体， 乙酰胆碱，或 GABA，如果是的话，精确的树突分布 将确定每个受体。 另外，模具精确分布 化学鉴定的皮质投射神经元传入神经元 将被确定。 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 几种不同类别的皮质投射神经元。 经过 考虑位置、连接性（突触输入和传出目标）， 形态学、生化表型、皮质亚型 可以定义投影细胞及其对给定的相对贡献 可以确定皮质投射。 我们预测 给定细胞的综合概况，以及给定的投影， 与其在正常皮质功能中的作用及其 AD 或其他神经退行性疾病的脆弱性。 如果我们可以 查明生化和解剖表型的要素 与 AD 中不同的细胞脆弱性最明显相关，那么我们 距离开发保护这些神经元的方法又近了一步 在AD中退化。 对这些神经元的保护必须是 制定 AD 管理策略的首要目标，因为 预防神经退行性疾病的可能性更大 比开发治愈方法更容易实现。