INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
J Neurochem. 2012 Jan;120 Suppl 1:99-108. doi: 10.1111/j.1471-4159.2011.07584.x. Epub 2011 Dec 7.
Amyloid peptide (Aβ) is derived from the cleavage of amyloid precursor protein (APP), which also generates the soluble peptide APPβ (sAPPβ). An antagonist and major APP metabolic pathway involves cleavage by alpha secretase, which releases sAPPα. Although soluble Aβ oligomers are neurotoxic, Aβ monomers share similar properties with sAPPα. These include neurotrophic and neuroprotective effects, as well as stimulation of neural-progenitor proliferation. The properties of Aβ monomers and the neurotrophic capacity of sAPPβ to stimulate axonal outgrowth suggest that Aβ production is not deleterious per se. Consequently, therapeutic strategies for Alzheimer's disease that are targeted at Aβ-cleaving enzymes should modulate rather than inhibit Aβ generation. These strategies should focus on the factors that induce the conversion of Aβ monomers into toxic soluble oligomers. Another interesting therapeutic approach is to focus on the mechanisms of the different properties of sAPPα. Indeed, increasing sAPPα levels could shift proliferating cells towards tumorigenesis. In contrast to its neuroprotective effects, sAPPα is also able to activate microglia, leading to neurotoxicity. Understanding the mechanisms that underlie the different properties of sAPPα could therefore lead to the development of therapeutic strategies against Alzheimer's disease, which could be curative as well as preventive.
淀粉样肽（Aβ）来源于淀粉样前体蛋白（APP）的裂解，APP 还生成可溶性肽 APPβ（sAPPβ）。一种拮抗剂和主要的 APP 代谢途径涉及α 分泌酶的裂解，释放 sAPPα。虽然可溶性 Aβ 寡聚物具有神经毒性，但 Aβ 单体与 sAPPα 具有相似的性质。这些性质包括神经营养和神经保护作用，以及刺激神经祖细胞增殖。Aβ 单体的性质和 sAPPβ 刺激轴突生长的神经营养能力表明，Aβ 的产生本身并不是有害的。因此，针对 Aβ 裂解酶的阿尔茨海默病治疗策略应该调节而不是抑制 Aβ 的产生。这些策略应该集中在诱导 Aβ 单体转化为有毒可溶性寡聚物的因素上。另一种有趣的治疗方法是关注 sAPPα 不同性质的机制。事实上，增加 sAPPα 水平可能会促使增殖细胞向肿瘤发生转化。与神经保护作用相反，sAPPα 还能够激活小胶质细胞，导致神经毒性。因此，了解 sAPPα 不同性质的机制可能会导致针对阿尔茨海默病的治疗策略的发展，这些策略既可以治疗又可以预防。
