McLean C A, Cherny R A, Fraser F W, Fuller S J, Smith M J, Beyreuther K, Bush A I, Masters C L
Department of Pathology, University of Melbourne, Victoria, Australia.
Ann Neurol. 1999 Dec;46(6):860-6. doi: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m.
Genetic evidence strongly supports the view that Abeta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Abeta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Abeta were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Abeta is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Abeta (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Abeta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Abeta that cause neurodegeneration. Reducing the levels of these soluble Abeta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.
遗传学证据有力地支持了这样一种观点，即β淀粉样蛋白的产生是阿尔茨海默病病因的核心。β淀粉样蛋白的动力学、分隔、形式及其与神经退行性过程的时间关系仍不明确。采用蛋白质印迹技术测定可溶性和不溶性β淀粉样蛋白的水平，并根据疾病严重程度指标对结果进行评估。在阿尔茨海默病中，可溶性β淀粉样蛋白的平均水平增加了两倍，且与疾病严重程度标志物高度相关。相比之下，不溶性β淀粉样蛋白的水平（也是总淀粉样蛋白负荷的一种度量）仅用于区分阿尔茨海默病与对照，与疾病严重程度或淀粉样斑块数量无关。这些发现支持了β淀粉样蛋白存在多个相互作用池的概念，即一个相对较大的静态不溶性池，它来自于一个不断更新的较小可溶性池。后者可能存在于细胞内和细胞外区室中，并包含导致神经退行性变的β淀粉样蛋白的基本形式。将这些可溶性β淀粉样蛋白物种的水平降低两倍至正常对照中的水平可能是未来治疗干预的目标。
