Small D H, Nurcombe V, Clarris H, Beyreuther K, Masters C L
Department of Pathology, University of Melbourne, Victoria, Australia.
Ann N Y Acad Sci. 1993 Sep 24;695:169-74. doi: 10.1111/j.1749-6632.1993.tb23047.x.
Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid plaques, which contain a protein referred to as the amyloid or beta A4 protein. The beta A4 protein is derived from a larger precursor protein (APP). Studies of autosomal-dominant forms of AD have established the central role of APP in the pathogenesis of the disease. Despite considerable research, the function of APP is unknown. APP can be processed by at least two separate routes. The first route involves a protease known as "APP secretase," which cleaves within the amyloid sequence, thereby mitigating amyloid formation. The second route may result in the production of potentially amyloidogenic fragments. Our studies suggest that following release from the cell membrane, APP interacts with components of the extracellular matrix (ECM) such as the heparan sulfate proteoglycans (HSPG's). The interaction of APP with HSPG's may be important for the function of APP. Substratum-bound APP was found to dramatically increase neurite outgrowth and survival of chick sympathetic neurons in vitro. This effect was dependent upon the presence of substratum-bound HSPG. The results suggest that normally, when bound to the ECM, APP functions to promote neurite outgrowth and/or cell survival. Loss of this normal trophic function might occur in AD, when APP is proteolytically processed via the amyloidogenic pathway.
阿尔茨海默病（AD）的特征是存在细胞外淀粉样斑块，其包含一种称为淀粉样蛋白或β - A4蛋白的蛋白质。β - A4蛋白源自一种更大的前体蛋白（APP）。对AD常染色体显性形式的研究已确定APP在该疾病发病机制中的核心作用。尽管进行了大量研究，但APP的功能仍不清楚。APP可通过至少两条不同途径进行加工。第一条途径涉及一种称为“APP分泌酶”的蛋白酶，它在淀粉样序列内切割，从而减少淀粉样蛋白的形成。第二条途径可能导致产生潜在的淀粉样生成片段。我们的研究表明，从细胞膜释放后，APP与细胞外基质（ECM）的成分如硫酸乙酰肝素蛋白聚糖（HSPG）相互作用。APP与HSPG的相互作用可能对APP的功能很重要。发现基质结合的APP在体外可显著增加鸡交感神经元的神经突生长和存活。这种效应依赖于基质结合的HSPG的存在。结果表明，正常情况下，当与ECM结合时，APP起到促进神经突生长和/或细胞存活的作用。当APP通过淀粉样生成途径进行蛋白水解加工时，AD中可能会丧失这种正常的营养功能。
