Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion

Significance

Autophagy is a catabolic process involving the formation of double-membrane–bound organelles called autophagosomes, which participate in the degradation of intracellular material through fusion with lysosomes. We have found a level of regulation of autophagosomal–lysosomal fusion where Presenilin 1 (PS1) phosphorylated at Ser367 specifically binds Annexin A2, which, through successive binding steps, facilitates this fusion. Lack of phosphorylation on PS1 1 Ser367 causes accumulation of partially fused autophagosomes and lysosomes in mouse brain and reduced autophagic flux. This inhibition of autophagy leads to decreased βCTF degradation and accumulation of toxic Aβ-peptide in the brain. This signaling pathway offers new potential drug targets for Alzheimer’s disease.

Abstract

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.