School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea.
The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel; The Pauld Feder Laboratory on Alzheimer's Disease Research, Israel.
Pharmacol Ther. 2022 Jul;235:108122. doi: 10.1016/j.pharmthera.2022.108122. Epub 2022 Feb 1.
Amyloid precursor protein (APP) is an evolutionarily conserved transmembrane protein and a well-characterized precursor protein of amyloid-beta (Aβ) peptides, which accumulate in the brains of individuals with Alzheimer's disease (AD)-related pathologies. Aβ has been extensively investigated since the amyloid hypothesis in AD was proposed. Besides Aβ, previous studies on APP and its proteolytic cleavage products have suggested their diverse pathological and physiological functions. However, their roles still have not been thoroughly understood. In this review, we extensively discuss the evolutionarily-conserved biology of APP, including its structure and processing pathway, as well as recent findings on the physiological roles of APP and its fragments in the central nervous system and peripheral nervous system. We have also elaborated upon the current status of APP-targeted therapeutic approaches for AD treatment by discussing inhibitors of several proteases participating in APP processing, including α-, β-, and γ-secretases. Finally, we have highlighted the future perspectives pertaining to further research and the potential clinical role of APP.
淀粉样前体蛋白（APP）是一种进化上保守的跨膜蛋白，也是淀粉样β（Aβ）肽的一种特征性前体蛋白，Aβ 在阿尔茨海默病（AD）相关病理患者的大脑中积累。自 AD 的淀粉样假说提出以来，Aβ 已经得到了广泛的研究。除了 Aβ 之外，先前对 APP 及其蛋白水解裂解产物的研究表明它们具有多种病理和生理功能。然而，其作用仍未被彻底理解。在这篇综述中，我们广泛讨论了 APP 的进化保守生物学，包括其结构和加工途径，以及 APP 和其片段在中枢神经系统和周围神经系统中的生理作用的最新发现。我们还通过讨论参与 APP 加工的几种蛋白酶抑制剂，包括α-、β-和γ-分泌酶，阐述了针对 AD 治疗的 APP 靶向治疗方法的现状。最后，我们强调了进一步研究和 APP 潜在临床作用的未来展望。
