Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts

被引:49
作者
Kosicek, Marko
Malnar, Martina
Goate, Alison [2 ]
Hecimovic, Silva [1 ]
机构
[1] Rudjer Boskovic Inst, Div Mol Med, Lab Mol Neuropharmacol, Zagreb 10000, Croatia
[2] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
关键词
Alzheimer's disease; Amyloid-beta; APP; Cholesterol; Lipid rafts; Niemann Pick type C disease; NPC1; AMYLOID BETA-PROTEIN; PRECURSOR PROTEIN; GAMMA-SECRETASE; TRANSPORT; DISEASE; TRAFFICKING; MUTATIONS; DEPLETION; DENSITY; GOLGI;
D O I
10.1016/j.bbrc.2010.02.007
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
It has been suggested that cholesterol may modulate amyloid-beta (A beta) formation, a causative factor of Alzheimer's disease (AD), by regulating distribution of the three key proteins in the pathogenesis of AD (beta-amyloid precursor protein (APP), beta-secretase (BACE1) and/or presenilin 1 (PS1)) within lipid rafts. In this work we tested whether cholesterol accumulation upon NPC1 dysfunction, which causes Niemann Pick type C disease (NPC), causes increased partitioning of APP into lipid rafts leading to increased CTF/A beta formation in these cholesterol-rich membrane microdomains. To test this we used CHO NPC1(-/-) cells (NPC cells) and parental CHOwt cells. By sucrose density gradient centrifugation we observed a shift in fl-APP/CTF compartmentalization into lipid raft fractions upon cholesterol accumulation in NPC vs. wt cells. Furthermore, gamma-secretase inhibitor treatment significantly increased fl-APP/CTF distribution in raft fractions in NPC vs. wt cells, suggesting that upon cholesterol accumulation in NPC1-null cells increased formation of APP-CTF and its increased processing towards A beta occurs in lipid rafts. Our results support that cholesterol overload, such as in NPC disease, leads to increased partitioning of APP/CTF into lipid rafts resulting in increased amyloidogenic processing of APP in these cholesterol-rich membranes. This work adds to the mechanism of the cholesterol-effect on APP processing and the pathogenesis of Alzheimer's disease and supports the role of lipid rafts in these processes. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:404 / 409
页数:6
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