Role of membrane lipids in regulation of Alzheimer’s disease associated proteins and vice-a-versa

Abstract

Alzheimer’s disease (AD) is associated with extracellular deposits of the amyloid β- peptide (Aβ) and intraneuronal aggregates of hyperphosphorylated tau protein in the brain. Aβ is generated by sequential proteolytic processing of the β-amyloid precursor protein (APP) by β- and γ-secretases. γ-secretase is a multimeric protein complex with presenilins as catalytic subunits, which cleave APP C-terminal fragments (APP-CTFs) generated by β-secretase cleavage of APP. Several studies have indicated dysregulation of protein transport and lipid metabolism as an important aspect of AD. The cleavage of APP by secretases which occurs predominantly in post-Golgi secretory and endocytic compartments is influenced by cholesterol, indicating a role of the membrane lipid composition in the processing of APP. Moreover, γ-secretase activity has been shown to be dependent on membrane lipids. In the present study, on one hand the effects of perturbations in membrane lipid composition on APP processing were analyzed in detail. On the other hand, the role of presenilins in maintenance of membrane lipid homeostasis was investigated as well. <br /> By various approaches, it was established that APP transport, stability, maturation and processing is affected by glycosphingolipids (GSLs). Importantly, the inhibition of GSL biosynthesis decreased secretion of Aβ, whereas addition of exogenous GSLs lead to higher Aβ levels as well as strong accumulation of APP-CTFs. Thus, the presented studies identified GSL metabolism as a novel target to regulate the levels of Aβ. Moreover, there is a growing perception that the increased levels of APP-CTFs contribute to AD pathology by exerting toxic effects. Elevated levels of APP-CTFs were also detected in various sphingolipid storage disorders (SLSDs). Interestingly, tau pathology and inflammation caused by microgliosis is observed both in AD as well as some sphingolipid storage disorders (SLSDs). Therefore, an accumulation of APPCTFs associated with altered sphingolipid metabolism might be an important common aspect of these disorders, which contributes to the observed neurodegeneration.<br /> In the course of these studies, a novel way by which presenilins regulate the cholesterol and sphingolipid metabolism was also revealed. Inhibition of γ-secretase activity results in inefficient endocytosis of LDL, which led to increased cellular de novo cholesterol biosynthesis via transcriptional up-regulation of CYP51. Evidence is provided for the global role of presenilins in regulation of endocytosis and degradation of membrane lipids and a broad range of proteins. The lack of γ-secretase activity causes an accumulation of membrane sphingolipids as well as membrane proteins. Thus, results validate the previously proposed hypothesis that presenilin are necessary for membrane protein clearance. Moreover, familial Alzheimer’s disease (FAD) associated mutations in presenilin disturbed the membrane lipid-protein homeostasis in a similar fashion by blocking endocytosis, indicating loss of function.<br /> The inhibition of γ-secretase activity is a rational strategy to decrease Aβ generation in AD therapy. However, since γ-secretase is involved in the cleavage of different substrates, a general inhibition of this enzyme could affect different biological processes. The finding that the inhibition of γ-secretase activity also impaired membrane lipid-protein homeostasis underscores the necessity of targeting γ-secretase cleavage of APP, without affecting other cellular pathways.