Presenilin 1 (PS1), the catalytic subunit of the γ-secretase complex, cleaves βCTF to produce Aβ. We have shown that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 decreases Aβ levels by increasing βCTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates βCTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8. Annexin A2 facilitates the binding of Vamp8 to the autophagosomal SNARE Syntaxin 17 to modulate the fusion of autophagosomes with lysosomes. Thus, PS1 phosphorylated at Ser367 has an antiamyloidogenic function, promoting autophagosome-lysosome fusion and increasing βCTF degradation. Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer's disease.Presenilin 1 | phosphorylation | autophagy | autophagosome-lysosome fusion | Annexin A2

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aβ), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aβ levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aβ levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aβ levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aβ levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aβ concentrations and confirmed that CK1γ2 activation effectively reduces their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.