Low-density lipoprotein receptor-related protein 8 (apolipoprotein E receptor 2) gene polymorphisms in Alzheimer’s disease Suk Ling Ma a,b , Ho Keung Ng c, * , Larry Baum d , Jesse Chung Sean Pang c , Helen Fung Kum Chiu b , Jean Woo d , Nelson Leung Sang Tang a , Linda Chiu Wa Lam b a DepartmentofAnatomicalandCellularPathology,FacultyofMedicine,TheChineseUniversityofHongKong,Shatin,HongKong,China b Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China c Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China d Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China Received 13 June 2002; received in revised form 9 August 2002; accepted 15 August 2002 Abstract Apolipoprotein E (ApoE) isoforms affect the risk of developing Alzheimer’s disease (AD). ApoE-associated risk may be related to its binding to and clearance by cell surface receptors, such as the members of the low-density lipoprotein (LDL) receptor family. Previous studies had shown association of LDL receptor-related protein (LRP) and AD, therefore we speculated that another member of this LDL receptor family, LRP8 (also called apolipoprotein E receptor 2 or ApoER2), which is predominantly expressed in brain, might be associated with Alzheimer’s disease. To explore this hypothesis, we screened exons 2–19 of the LRP8 gene in a total of 204 AD and 184 elderly control subjects for polymorphisms using the conformation-sensitive gel electrophoresis method. Our results revealed four sequence alterations: two predicted to result in amino acid changes (E46D and R952Q), one in an intron (IVS9 1 7G . A), and one synonymous polymorphism (2622T . C). The latter was found in four AD patients (2.0%) and 11 controls (6.0%), a significant difference (P ¼ 0:042). Further study is needed to confirm this possible association of LRP8 with AD. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Alzheimer’s disease; Polymorphism; Low-density lipoprotein; Receptor-related protein 8 Apolipoprotein E (ApoE) [10] is a 34-kDa polymorphic protein in the surface of circulating lipoprotein particles. In plasma, ApoE transports lipoproteins containing cholesterol and lipids to cells via binding to receptors such as the low- density lipoprotein receptor (LDLR) [10] and the LDL receptor-related protein/a 2 -macroglobulin receptor (LRP) [1,8,14]. In the central nervous system, ApoE is synthesized in astrocytes and is present in the cerebrospinal fluid [12]. Since the presence of ApoE allele 4 (14) or the LRP 766C allele is associated with an increased risk for Alzheimer’s disease (AD) [5,15], we speculated that polymorphisms in other ApoE receptors expressed in the brain might also be associated with the risk of AD. LRP8 (also called apolipoprotein E receptor 2 or ApoER2) is a recently cloned member of the low-density lipoprotein receptor family [7]. It is located on chromosome 1p34 and contains 19 exons which span a genomic region of about 60 kb. It consists of five domains that resemble those of the LDLR and the very low density lipoprotein (VLDL) receptor [7]. LRP8 mRNA is predominantly expressed in brain and placenta [6]. Previous studies have shown that LRP8 parti- cipates in transmitting the extracellular Reelin signal to intra- cellular signaling processes initiated by Disabled-1 [4]. LRP8 knockout mice display disturbed neuronal organiza- tion in the hippocampus [2]. LRP8 immunoreactivity in human hippocampus is present exclusively in neurons and is increased in AD [11]. The c-Jun N-terminal kinase (JNK) pathway may transduce Ab neurotoxicity, and LRP8 binds JNK-interacting proteins, thus suggesting a possible involve- ment of LRP8 in AD pathophysiology [13,16]. Based on the possible involvement of LRP8 in AD, we undertook a case control study in which we scanned the coding regions of the LRP8 gene for polymorphisms associated with AD. The study included 204 Chinese AD patients (78% women; mean age at study, 78.5 ^ 8.3; range, 58–97) who were either clinically diagnosed by NINCDS/ADRDA criteria for probable AD or pathologically diagnosed as definite AD by the CERAD criteria. Control subjects were Neuroscience Letters 332 (2002) 216–218 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)00942-4 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 1852-26-323-337; fax: 1852-26- 376-274. E-mail address: hkng@cuhk.edu.hk (H.K. Ng).