Zhang Shuting, Cai Fang, Wu Yili, Bozorgmehr Tahereh, Wang Zhe, Zhang Si, Huang Daochao, Guo Jifeng, Shen Lu, Rankin Catharine, Tang Beisha, Song Weihong
Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Department of Psychiatry, Graduate Program in Psychiatry, Jining Medical University, Jining, China.
Mol Psychiatry. 2020 Mar;25(3):603-613. doi: 10.1038/s41380-018-0101-x. Epub 2018 Jun 18.
Presenilin-1 (PSEN1) is the catalytic subunit of the γ-secretase complex, and pathogenic mutations in the PSEN1 gene account for the majority cases of familial AD (FAD). FAD-associated mutant PSEN1 proteins have been shown to affect APP processing and Aβ generation and inhibit Notch1 cleavage and Notch signaling. In this report, we found that a PSEN1 mutation (S169del) altered APP processing and Aβ generation, and promoted neuritic plaque formation as well as learning and memory deficits in AD model mice. However, this mutation did not affect Notch1 cleavage and Notch signaling in vitro and in vivo. Taken together, we demonstrated that PSEN1 has distinct effects on APP processing and Notch1 cleavage, suggesting that Notch signaling may not be critical for AD pathogenesis and serine169 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch1 cleavage to treat AD.
早老素-1（PSEN1）是γ-分泌酶复合物的催化亚基，PSEN1基因中的致病性突变占家族性阿尔茨海默病（FAD）的大多数病例。已表明与FAD相关的突变型PSEN1蛋白会影响淀粉样前体蛋白（APP）的加工和β淀粉样蛋白（Aβ）的产生，并抑制Notch1的切割和Notch信号传导。在本报告中，我们发现一种PSEN1突变（S169del）改变了APP的加工和Aβ的产生，并促进了AD模型小鼠的神经炎性斑块形成以及学习和记忆缺陷。然而，这种突变在体外和体内均不影响Notch1的切割和Notch信号传导。综上所述，我们证明PSEN1对APP加工和Notch1切割具有不同的影响，这表明Notch信号传导可能对AD发病机制并不关键，丝氨酸169可能是一个关键位点，作为开发新型γ-分泌酶调节剂的潜在靶点，该调节剂在不影响Notch1切割的情况下治疗AD。
