Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice

被引:81
作者
Cao, Dongfeng
Fukuchi, Ken-ichiro
Wan, Hongquan
Kim, Helen
Li, Ling
机构
[1] Univ Alabama, Dept Med, Atherosclerosis Res Unit, Div Gerontol & Geriatr Med, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Genet, Birmingham, AL 35294 USA
[3] Univ Alabama, Dept Pharmacol, Birmingham, AL 35294 USA
[4] Univ Illinois, Coll Med, Dept Biomed Therapeut Sci, Peoria, IL 61656 USA
关键词
LDL receptor; behavioral assessment; learning and memory; amyloid deposition; transgenic mouse model;
D O I
10.1016/j.neurobiolaging.2005.09.011
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral beta-amyloidosis. Before the manifestation of amyloid-beta (A beta) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of A beta deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-beta precursor protein transgene, there was a significant increase in A beta deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:1632 / 1643
页数:12
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