Cerebral elevation of 42-residue amyloid β-peptide (Aβ42) triggers neuronal dysfunction in Alzheimer's disease (AD). Even though a number of cholesterol modulating agents have been shown to affect Aβ generation, the role of cholesterol in the pathogenesis of AD is not clear yet. Recently, we have shown that increased membrane cholesterol levels downregulates phosphatidylinositol 4,5-bisphosphate (PIP2) via activation of phospholipase C (PLC). In this study, we tested whether membrane cholesterol levels may affect the Aβ42 production via changing PIP2 levels. Increasing membrane cholesterol levels decreased PIP2 and increased secreted Aβ42. Supplying PIP2, by using a PIP2-carrier system, blocked the effect of cholesterol on Aβ42. We also found that cholesterol increased the expressions of β1 and β3 PLC isoforms (PLCβ1, PLCβ3). Silencing the expression of PLCβ1 prevented the effects of cholesterol on PIP2 levels as well as on Aβ42 production, suggesting that increased membrane cholesterol levels increased secreted Aβ42 by downregulating PIP2 via enhancing the expression of PLCβ1. Thus, cholesterol metabolism may be linked to Aβ42 levels via PLCβ1 expression and subsequent changes in PIP2 metabolism. 1. Introduction AD is a progressive and irreversible neurodegenerative disorder leading to cognitive, memory, and behavioral impairments. Cerebral elevation and accumulation of Aβ are necessary steps in the pathogenesis of AD [1–3]. Sequential proteolytic cleavages of amyloid precursor protein (APP) by membrane-bound β-secretase and γ-secretase produce two major isoforms of Aβ, Aβ40, and Aβ42. Therefore, this pathway is called amyloidogenic pathway. More amyloidogenic Aβ42 is considered as a pathogenic agent [4, 5]. Alternatively, APP can be sequentially processed by α-secretase, and γ-secretase, precluding Aβ production (nonamyloidogenic pathway). Even though advanced age serves as a major risk factor, approximately 5% of AD cases are familial (FAD), and some of them are attributable to autosomal dominant mutations in presenilin (PS) genes, PS1 and PS2. PS1 and PS2 function as catalytic subunits of γ-secretase, and FAD mutations in PSs affect APP processing increasing the ratio of Aβ42 to Aβ40 [6–8]. Growing evidence indicates that dysregulation of lipid pathways have regulatory consequences for APP processing and Aβ generation [9]. Especially, cholesterol has been suggested to participate in the etiology of AD by increasing the generation of Aβ [10]. Cholesterol can directly regulate the activities of β-secretase or γ-secretase to alter amyloidogenesis
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