Amyloid Accumulation Mechanisms/Pathogenesis in AD Brain

AD 脑中淀粉样蛋白积累机制/发病机制

• 批准号: 6587293
• 负责人: Charles G. Glabe
• 金额: $ 22.86万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6587293
• 关键词: Amyloid; Accumulation; Mechanisms; Pathogenesis; AD

DESCRIPTION (Adapted from the application): While it is well recognized that the accumulation of extracellular amyloid is a hallmark of AD, many of the key pathological events of AD may also be directly related to the intracellular accumulation of this insoluble peptide. Recent studies in cell culture have indicated that A-beta1-42 (but not A-beta1-40), once accumulated inside cells, is resistant to degradation and can serve as a nidus for a prion-like replication model (the solid phase replication model for A-beta accumulation). Further studies in brain suggest that A-beta1-42 is the preferential form that accumulates in AD and that A-beta can be found within neurons though much less is known about its state and associated proteins. Once present in cultured cells, the aggregated amyloid induces the production of reactive oxygen species and lipid peroxidation products and ultimately results in the leakage of the lysosomal membrane. The breakdown of the lysosomal membrane may be a key pathological event, leading to the release of heparan sulfate and lysosomal hydrolysases. Taken together, these observations provide the novel view that amyloid deposits and some of the early events of amyloid pathogenesis initiate randomly within single cells in AD. This mechanism can explain some of the more enigmatic features of AD pathogenesis, like the focal nature of amyloid plaques, dystrophic neurites and neurofibrillary tangle pathology and the miscompartmentation of extracellular and cytosolic components observed in the AD brain. This project will use a combination of biochemical and light and electron microscopic, immunocytochemical approaches to study the accumulation of intracellular amyloid. The studies will be a combination of in vitro on cultured cells and in vivo studies on control and-AD brain, thereby combining the precision of in vitro studies with the need to evaluate predictions and findings in vivo. Select experiments will also be conducted on the aged canine brain that accumulates extensive amyloid and where the postmortem conditions can be precisely controlled. Preliminary data support the hypothesis that amyloid ("preamyloid") accumulates in neurons in the aging and AD brain, can be shown to have a granular appearance in neurons and may be associated with a breakdown in intracellular compartmentation.

描述（改编自应用程序）：虽然它得到了广泛认可 细胞外淀粉样蛋白的积累是 AD 的一个标志，许多 AD的关键病理事件也可能与 这种不溶性肽在细胞内积累。最近的研究 细胞培养表明 A-beta1-42（但不是 A-beta1-40），一旦 积累在细胞内，抗降解，可以作为 类朊病毒复制模型的病巢（固相复制模型 用于 A-β 积累）。对大脑的进一步研究表明 A-beta1-42 是 AD 中积累的优先形式，A-β 可以是 尽管对其状态知之甚少，但在神经元中发现 相关蛋白质。一旦存在于培养细胞中，聚集的 淀粉样蛋白诱导活性氧和脂质的产生 过氧化产物，最终导致泄漏 溶酶体膜。溶酶体膜的破裂可能是关键 病理事件，导致硫酸乙酰肝素和溶酶体的释放 水解酶。总而言之，这些观察提供了新颖的观点 淀粉样蛋白沉积和淀粉样蛋白发病机制的一些早期事件 AD 中的单个细胞内随机启动。这个机制可以解释 AD 发病机制的一些更神秘的特征，例如局灶性 淀粉样蛋白斑、营养不良的神经突和神经原纤维缠结的性质 病理学以及细胞外和细胞质的错配 AD 大脑中观察到的成分。该项目将结合使用 生化和光电子显微镜、免疫细胞化学 研究细胞内淀粉样蛋白积累的方法。研究 将结合体外培养细胞和体内研究 控制和 AD 大脑，从而结合体外研究的精度 需要评估体内的预测和发现。选择 实验还将在老年犬的大脑上进行 积累大量的淀粉样蛋白，死后的情况可以 精确控制。初步数据支持淀粉样蛋白的假设 （“前淀粉样蛋白”）在衰老和 AD 大脑的神经元中积累，可以 显示在神经元中具有颗粒状外观，并且可能与 细胞内区室分裂。