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 PSEN1S169del 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.
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This work was supported by Canadian Institutes of Health Research (CIHR) Operating Grant CCI-117952,TAD-117948, and MOP-142487to WS and CIHR Operating Grant #122216-2013 to CR. WS was the holder of the Tier 1 Canada Research Chair in Alzheimer’s disease. Sh.Z. was the recipient of the Chinese Scholarship Council award. Si.Z. is supported by UBC 4YF Scholarship. Assistance in C. elegans egg-counting was provided by Mahraz Parvand and Dawson Born.
WS conceived and designed the experiments; ShZ, FC, YW, TB, ZW, SiZ, DH and WS performed the experiments; ShZ, FC, YW, TB, ZW, SiZ, JG, LS, BT, CR and WS analyzed and contributed reagents /materials /analysis tools; ShZ, FC, YW, CR and WS wrote the paper. All authors reviewed the manuscript.
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The authors declare that they have no conflict of interest.
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Zhang, S., Cai, F., Wu, Y. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol Psychiatry 25, 603–613 (2020). https://doi.org/10.1038/s41380-018-0101-x
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