Amyloid Accumulation Mechanisms/Pathogenesis in AD Brain

描述(改编自应用程序)：尽管它很容易被识别 细胞外淀粉样蛋白的积累是阿尔茨海默病的一个标志，许多 阿尔茨海默病的关键病理事件也可能与 这种不溶于水的多肽在细胞内积累。最近的研究 细胞培养表明A-β1-42(但不是A-β1-40)，曾经 积聚在细胞内，耐降解，可用作 Pron-like复制模型(固相复制模型)的NIDUS 用于A-β累积)。对大脑的进一步研究表明，A-β1-42 是在AD中积累的优先形式，A-β可以是 在神经元中发现的，尽管对其状态和 相关蛋白质。一旦出现在培养的细胞中，聚集的 淀粉样蛋白诱导活性氧和脂质的产生 过氧化产物，并最终导致泄漏 溶酶体膜。溶酶体膜的破裂可能是一个关键 病理事件，导致硫酸乙酰肝素和溶酶体的释放 水解酶。综上所述，这些观察提供了一种新颖的观点 淀粉样蛋白沉积与淀粉样蛋白发病的一些早期事件 在AD的单个细胞内随机启动。这一机制可以解释 阿尔茨海默病发病机制的一些更神秘的特征，如局部 淀粉样斑块、营养不良轴突和神经原纤维缠结的性质 细胞外和胞内的病理与细胞内的分隔 在阿尔茨海默病大脑中观察到的成分。该项目将结合使用 生化、光镜和电子显微镜、免疫细胞化学 研究细胞内淀粉样蛋白蓄积的方法。这些研究 将是体外培养细胞和体内研究的结合 对照和AD大脑，从而结合了体外研究的精确度 需要评估体内的预测和发现。选择 实验还将在老化的犬脑上进行， 积聚了大量的淀粉样蛋白和尸检条件 精确控制。初步数据支持淀粉样蛋白的假说 (“preyloid”)积聚在衰老和AD大脑中的神经元中，可以 在神经元中有颗粒状外观，并可能与 细胞内分隔的分解。

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.