Amyloid Abeta in the natural history of Alzheimer's disease

这项拨款是为了揭示阿尔茨海默病的基本原因而进行的一系列大型实验的延续。我们的重点是缩小我们对阿尔茨海默病的自然历史与大脑中β淀粉样蛋白沉积的认识上的一些差距，我们认为β淀粉样蛋白在这种情况下的神经细胞退化中起着核心作用。我们正在解决的主要问题包括：使用血液中β检测作为阿尔茨海默病的生物标志物的可行性；是否需要更好的阿尔茨海默病转基因小鼠模型；β -淀粉样蛋白的可溶形式是否是导致神经毒性的主要种类（与在阿尔茨海默氏症患者大脑中构成该蛋白大部分的不可溶形式形成对比）；以及β聚集的细胞内或细胞外途径和毒性是了解这种疾病的关键。越来越多的证据表明，从大脑中清除可溶性的β蛋白可能是一种主要的治疗策略。因此，我们需要进一步研究这些可溶性形式的β是如何在神经细胞中产生的，以及这些形式是如何与大脑、脑脊液、血液和身体其他组织中的可溶性和不可溶性池平衡存在的。

This grant is the continuation of a large series of experiments designed to uncover the basic causes of Alzheimer's disease. The focus is on closing some of the gaps in our knowledge of the natural history of Alzheimer's disease in relation to the deposition of the Abeta amyloid protein in the brain, which we believe plays a central role in the degeneration of nerve cells in this condition. The main questions we are tackling include: the feasibility of using assays of Abeta in the blood as a biological marker of Alzheimer's disease; whether better transgenic mouse models of Alzheimer's disease are required; whether the soluble forms of Abeta amyloid are the major species which cause neurotoxicity (in contrast to the insoluble forms which constitute the bulk of this protein in the Alzheimer's disease brain); and whether the intracellular or extracellular pathways of Abeta aggregation and toxicity are the key to understanding this disease. Increasing evidence suggests that the clearance of soluble forms of the Abeta protein from the brain may be a major therapeutic strategy. We therefore require further investigations of how these soluble forms of Abeta are generated in nerve cells, and how these forms exist in equilibrium with soluble and insoluble pools in the brain, cerebrospinal fluid, blood and other tissues of the body.