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

Presenilin 1 (PS1), the catalytic subunit of the gamma-secretase complex, cleaves beta CTF to produce A beta. We have shown that PS1 regulates A beta levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the.-secretase complex, selective phosphorylation of PS1 on Ser367 decreases A beta levels by increasing beta CTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates beta CTF 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 beta CTF degradation. Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer's disease.