Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice.
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 (Abeta) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Abeta 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 Abeta 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.
Cao
Dongfeng
D
Atherosclerosis Research Unit, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South, BDB 658, Birmingham, AL 35294, USA.
Fukuchi
Ken-ichiro
K
Wan
Hongquan
H
Kim
Helen
H
Li
Ling
L
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000686:Amyloidosis / Q000473:pathology*; D000818:Animals; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000473:pathology; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000097:blood / Q000172:deficiency*
D016229:Amyloid beta-Peptides; D011973:Receptors, LDL; D002784:Cholesterol