Neurobiology of Aging xxx (2005) xxx–xxx Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice Dongfeng Cao a , Ken-ichiro Fukuchi b,d , Hongquan Wan a , Helen Kim c , Ling Li a,∗ a 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 b Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA c Department of Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294, USA d Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA Received 3 April 2005; received in revised form 3 August 2005; accepted 9 September 2005 Abstract 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 -amyloidosis. Before the manifestation of amyloid- (A) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of A 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- precursor protein transgene, there was a significant increase in A 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. © 2005 Elsevier Inc. All rights reserved. Keywords: LDL receptor; Behavioral assessment; Learning and memory; Amyloid deposition; Transgenic mouse model 1. Introduction Alzheimer’s disease (AD) is a common age-related neu- rodegenerative disorder characterized clinically by progres- sive cognitive impairment. Pathological hallmarks of AD brain include neurofibrillary tangles and deposits of aggre- gated amyloid- protein (A) in neuritic plaques and cerebral vessels [37]. The pathogenic mechanisms that lead to the development of AD, however, are not fully understood. One of the main hypotheses is that -amyloidosis (production and deposition of A) plays a crucial role in the pathogenesis of AD [37].A (39–43 amino acids) is derived from a large transmembrane glycoprotein, amyloid- precursor protein (APP), by proteolytic processing. ∗ Corresponding author. Tel.: +1 205 934 1889; fax: +1 205 975 8079. E-mail address: lili@uab.edu (L. Li). Accumulating evidence indicates that cholesterol is closely involved in the development of AD. Early epi- demiological data indicate an increased prevalence of cerebral senile plaques in cognitively intact individuals with heart disease compared to age-matched controls with no heart disease [40], suggesting a possible link between high plasma cholesterol levels and cerebral amyloidosis. The apolipoprotein (apo) E4 allele, a strong risk factor for AD [7], is also associated with hypercholesterolemia and atherosclerosis [7]. Elevated plasma cholesterol levels have been shown to be an independent risk factor for AD [28]. In vitro evidence also links cholesterol with APP processing and amyloid deposition [3,8,9,21,39]. Experimentally, dietary-induced hypercholesterolemia induces the formation of A deposition in the brain of rabbits [41]. Recently, we and others have demonstrated that high fat/high cholesterol diets exacerbate cerebral -amyloidosis in APP transgenic mice [23,24,33,38]. We also have shown that an atherogenic 0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2005.09.011 NBA-6392; No. of Pages 12