A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling

• Published in: Molecular psychiatry Vol. 25; no. 3; pp. 603 - 613
• Main Authors: Zhang, Shuting, Cai, Fang, Wu, Yili, Bozorgmehr, Tahereh, Wang, Zhe, Zhang, Si, Huang, Daochao, Guo, Jifeng, Shen, Lu, Rankin, Catharine, Tang, Beisha, Song, Weihong
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2020
• Subjects: Advertising executives; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Protein Precursor - genetics; Amyloid precursor protein; Amyloid Precursor Protein Secretases - metabolism; Animal models; Animals; Female; Genetic aspects; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutants; Mutation; Neurodegenerative diseases; Notch1 protein; Presenilin 1; Presenilin-1 - genetics; Presenilin-1 - metabolism; Proteins; Receptors, Notch - metabolism; Receptors, Notch - physiology; Secretase; Signal Transduction - genetics; Sulindac; Wang Zhe
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-018-0101-x

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.