Bidirectional regulation of Aβ levels by Presenilin 1

Alzheimer's disease (AD) is characterized by accumulation of the beta-amyloid peptide (A beta), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of beta-secretase, generating the beta-C-terminal fragment (beta CTF), and then by the Presenilin 1 (PS1) enzyme in the gamma-secretase complex, generating A beta. gamma-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect gamma-secretase activity, but has a dramatic effect on A beta levels in vivo. We identified CK1 gamma 2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1 gamma leads to a decrease in PS1 Ser367 phosphorylation and an increase in A beta levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in A beta peptide and in beta CTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of beta CTF, resulting in its accumulation and increased levels of A beta peptide and plaque load in the brain. Our results demonstrate 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 also decreases A beta levels by increasing beta CTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates beta CTF degradation may aid in the development of potential therapies for Alzheimer's disease.