%0 Journal Article
%T Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C
%A Yoon Sun Chun
%A Hyun Geun Oh
%A Myoung Kyu Park
%A Tae-Wan Kim
%A Sungkwon Chung
%J Journal of Neurodegenerative Diseases
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/407903
%X Cerebral elevation of 42-residue amyloid ¦Â-peptide (A¦Â42) triggers neuronal dysfunction in Alzheimer's disease (AD). Even though a number of cholesterol modulating agents have been shown to affect A¦Â 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 A¦Â42 production via changing PIP2 levels. Increasing membrane cholesterol levels decreased PIP2 and increased secreted A¦Â42. Supplying PIP2, by using a PIP2-carrier system, blocked the effect of cholesterol on A¦Â42. We also found that cholesterol increased the expressions of ¦Â1 and ¦Â3 PLC isoforms (PLC¦Â1, PLC¦Â3). Silencing the expression of PLC¦Â1 prevented the effects of cholesterol on PIP2 levels as well as on A¦Â42 production, suggesting that increased membrane cholesterol levels increased secreted A¦Â42 by downregulating PIP2 via enhancing the expression of PLC¦Â1. Thus, cholesterol metabolism may be linked to A¦Â42 levels via PLC¦Â1 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 A¦Â are necessary steps in the pathogenesis of AD [1¨C3]. Sequential proteolytic cleavages of amyloid precursor protein (APP) by membrane-bound ¦Â-secretase and ¦Ã-secretase produce two major isoforms of A¦Â, A¦Â40, and A¦Â42. Therefore, this pathway is called amyloidogenic pathway. More amyloidogenic A¦Â42 is considered as a pathogenic agent [4, 5]. Alternatively, APP can be sequentially processed by ¦Á-secretase, and ¦Ã-secretase, precluding A¦Â 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 ¦Ã-secretase, and FAD mutations in PSs affect APP processing increasing the ratio of A¦Â42 to A¦Â40 [6¨C8]. Growing evidence indicates that dysregulation of lipid pathways have regulatory consequences for APP processing and A¦Â generation [9]. Especially, cholesterol has been suggested to participate in the etiology of AD by increasing the generation of A¦Â [10]. Cholesterol can directly regulate the activities of ¦Â-secretase or ¦Ã-secretase to alter amyloidogenesis
%U http://www.hindawi.com/journals/jnd/2013/407903/