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

Abstract

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.

BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis

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Identification of Alzheimer’s disease–associated rare coding variants in the ECE2 gene

“…Antibody 9E10 (Abcam, catalog ab32) was used to detect Myc-tagged proteins. APP and its C-terminal fragment products were detected with C20 antibody (57). β-Actin was detected with monoclonal antibody AC-15 (Sigma-Aldrich).…”

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