Bidirectional regulation of Aß levels by Presenilin 1.

ABSTRACT

Alzheimer's disease (AD) is characterized by accumulation of the ß-amyloid peptide (Aß), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of ß-secretase, generating the ß-C-terminal fragment (ßCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aß. γ-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 γ-secretase activity, but has a dramatic effect on Aß levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aß levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aß peptide and in ßCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of ßCTF, resulting in its accumulation and increased levels of Aß peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aß 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 also decreases Aß levels by increasing ßCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates ßCTF degradation may aid in the development of potential therapies for Alzheimer's disease.