St George-Hyslop P H, McLaurin J, Fraser P E
Centre for Research in Neurodegenerative Diseases, Crescent West, University of Toronto, Toronto, Ontario, Canada.
Drug News Perspect. 2000 Jun;13(5):281-8.
The molecular and cellular processes that lead to the production of the amyloid beta (A beta) peptide and some of the processes associated with A beta fibrillogenesis and neurotoxicity have recently been elucidated. Experimental results have suggested that abnormalities in the processing of the beta-amyloid precursor protein (beta APP) are central to the pathogenesis of Alzheimer's disease (AD). beta APP processing includes two mutually exclusive proteolytic cleavage pathways, one involving the putative gamma-secretase enzyme, the identity of which remains unknown. Recent evidence has suggested the presenilin 1 and presenilin 2 genes are necessary for gamma-secretase activities. Another gene associated with susceptibility to AD is the apolipoprotein E (APOE) gene. Given the important role that abnormal processing of beta APP plays in the genesis of AD, most current efforts are directed at either modulating A beta peptide production or inhibiting its ability to aggregate into fibrils and cause neurotoxicity. To inhibit A beta production, one strategy might be to inhibit either beta-secretase or gamma-secretase. Several approaches to the inhibition of A beta aggregation are under investigation.
导致β淀粉样蛋白（Aβ）肽产生的分子和细胞过程以及一些与Aβ纤维形成和神经毒性相关的过程最近已被阐明。实验结果表明，β淀粉样前体蛋白（βAPP）加工过程中的异常是阿尔茨海默病（AD）发病机制的核心。βAPP加工包括两条相互排斥的蛋白水解切割途径，其中一条涉及假定的γ-分泌酶，其身份仍然未知。最近的证据表明，早老素1和早老素2基因对于γ-分泌酶活性是必需的。另一个与AD易感性相关的基因是载脂蛋白E（APOE）基因。鉴于βAPP异常加工在AD发生中所起的重要作用，目前大多数努力都致力于调节Aβ肽的产生或抑制其聚集形成纤维并导致神经毒性的能力。为了抑制Aβ的产生，一种策略可能是抑制β-分泌酶或γ-分泌酶。目前正在研究几种抑制Aβ聚集的方法。
