A role of Alzheimer’s disease-associated γ-secretase in lipid metabolism and lipid droplet formation via LXR activation

Abstract

The γ secretase is an intramembrane protease complex, essential for the processing of a wide variety of type-1 membrane proteins. Among these is the amyloid precursor protein (APP), a protein strongly linked to Alzheimer’s disease (AD), both for the role of the APP gene in the development of early-onset AD, as well as for being the precursor of the amyloid-β peptide, produced through sequential processing by β and γ-secretases. The primary catalytical proteins of the γ-secretase complex are Presenilins (PS). Interestingly, mutations in the PS genes are associated with the development of autosomal dominant forms of early-onset AD. However, the mechanisms by which APP and PS contribute to the pathogenesis of AD are not fully understood, nor are the cellular roles of APP or its cleavage by γ-secretase. Previous reports have revealed a link between PS and cellular lipid metabolism, with a lack of PS activity leading to dysregulation of cholesterol metabolism and lipoprotein endocytosis. This study revealed how a lack of PS activity leads to an elevation of lipid droplet levels, triglyceride levels, cholesterol metabolite levels and cholesterol secretion, as well as a decrease in cholesterol esterification. These observations are shown to involve an increment of LXR activity. In particular, cells lacking PS activity display a substantial elevation of LXR protein levels, as well as of transcripts of LXR target genes involved in sterol and triglyceride metabolism. Additional experiments showed that the APP C-terminal fragment C99 (C99), a substrate of γ-secretase, accumulate in cholesterol-rich, AP-1 positive vesicles upon pharmacological inhibition of γ-secretase. The cellular levels of C99 positively correlate with an increase in lipid droplet levels, suggesting that C99 accumulation is involved in the alterations of lipid metabolism observed upon inhibition of γ-secretase activity. Together, our findings reveal a mechanism that functionally connects γ-secretase-dependent cleavage of the APP C-terminal fragment to cellular sterol and lipoprotein metabolism, which could potentially contribute to the pathogenesis of AD.