Neurochemistry International 50 (2007) 12–38 www.elsevier.com/locate/neuint Review Convergence of genes implicated in Alzheimer’s disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis C.J. Carter 176 Downs Road, Hastings, East Sussex TN34 2DZ, UK Received 5 April 2006; received in revised form 30 June 2006; accepted 11 July 2006 Available online 12 September 2006 Abstract Polymorphic genes associated with Alzheimer’s disease (see www.polygenicpathways.co.uk) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer’s disease, may play a major role in its pathology. Many other genes associated with Alzheimer’s disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer’s disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer’s disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464–479.]. Thus, the fact that Alzheimer’s disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies. # 2006 Elsevier Ltd. All rights reserved. Keywords: Alzheimer’s disease; Atherosclerosis; Cholesterol metabolism; Lipoprotein; Cholesterol shuttle 1. Introduction part of a protease complex that degrades APP. One of the functional effects of the mutations in APP, PSEN1 and PSEN2 Mutations in amyloid precusor protein (APP) and the is to increase the degradation of APP to potentially toxic presenilins, PSEN1 and PSEN2 have been shown to be neuropeptides (beta amyloid) that are a major component of responsible for a number of familial Alzheimer’s disease cases amyloid plaque in the Alzheimer’s disease brain (Tanzi and and different apolipoprotein E (APOE 1–4) alleles strongly Bertram, 2001). Apolipoprotein E (APOE) also interacts with influences the incidence of Alzheimer’s disease. Presenilin is APP and beta amyloid (Haas et al., 1997). Because of these relationships in key genes relating to pathology, the amyloid hypothesis of Alzheimer’s disease has now held centre stage for E-mail address: [email protected]. some time. Briefly stated, defective APP processing leads to the 0197-0186/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2006.07.007 C.J. Carter / Neurochemistry International 50 (2007) 12–38 13 generation of neurotoxic insoluble beta-amyloid peptides that been associated with Alzheimer’s disease, in at least one study, accumulate in the senile plaques that characterise the disease although their role as susceptibility factors is often contested (Hardy and Selkoe, 2002). because of conflicting genetic data in different populations (see Recent studies have suggested that cholesterol lowering below). These genes are listed in Tables 1–8 together with a agents (3-hydroxy-3-methylglutaryl coenzyme A reductase brief summary of their main effects, interactions, and (HMGCR) inhibitors or statins) (Dufouil et al., 2005; Sparks relationship to APP, cholesterol, and lipoprotein function. et al., 2005a; Sjogren et al., 2003; Wolozin et al., 2000; Zamrini Examples of references to positive association studies are et al., 2004) or a diet rich in fish or n À 3 unsaturated fatty acids posted at a supplementary Website at http://www.polygenic- (Morris et al., 2003b) can reduce the incidence of Alzheimer’s pathways.co.uk/alzpolys.html. These website tables also disease. Negative studies with statins have also been reported provide the chromosomal location of each gene and references (Zandi et al., 2005; Rea et al., 2005; Scott and Laake, 2001; for linkage data implicating this region in Alzheimer’s disease, Sparks et al., 2005b) and the results of more extensive clinical where available. A brief summary of expression and functional trials are eagerly awaited. Conversely, obesity is a risk factor for data is also provided. Because of the large number of references Alzheimer’s disease in women (Gustafson et al., 2003) and the generated by so many genes, some citations in the text of this dietary intake of saturated fatty acids increases the risk for manuscript are collectively referenced by this website (Carter, Alzheimer’s disease (Morris et al., 2003a). Whether, and how, 2006). All positive and negative association studies can be these factors modify the incidence of Alzheimer’s disease all viewed at the Alzgene website (http://www.alzforum.org) require further study. (Bertram et al., 2005). As shown below, many of these genes Alzheimer’s disease also has a significant vascular (including APP and the beta and gamma secretases) can be component. Other authors have pointed out the link between assembled to form most of the components of a glial/neuronal atherosclerosis and Alzheimer’s disease, which share common cholesterol shuttle whose function specifically relates to the gene associations and risk factors and vascular problems control of cerebral cholesterol homoeostasis. Many of these (Casserly and Topol, 2004; de la Torre, 2004). The changes in same genes are also involved in atherosclerosis. It is recognised these indices of cholesterol and lipoprotein function in that the multiple other properties of some of these components Alzheimer’s disease are subtle and less evident than observed are also likely to play a role in the multifactorial pathology of for other cholesterol/lipoprotein disorders such as athero- Alzheimer’s disease (Cacabelos et al., 2005). These properties sclerosis, cardiovascular and cerebrovascular disease. As are not addressed in this review, which focuses on cholesterol pointed out by Pappolla et al. (2003) it is likely that larger and lipoprotein function to illustrate the convergence of many changes in cholesterol/lipoprotein function would be fatal genes on this area. Genes associated with Alzheimer’s disease before Alzheimer’s disease could develop and that cholesterol/ are shown in bold in the subsequent text. Gene symbols are Alzheimer’s disease associations would be masked by this those of the HUGO gene nomenclature committee (Wain et al., effect. The atherosclerosis link is supported by a close 2002). correlation between atherosclerotic markers and dementia, vascular dementia and Alzheimer’s disease (Hofman et al., 2. Heterogeneity in association studies and reasons for 1997). In this study, including 207 Alzheimer’s disease including all positively associated genes patients, indices of peripheral atherosclerosis including carotid artery plaques, carotid artery wall thickness and a combined The definition of most of the genes used to create the atherosclerosis score were all correlated with Alzheimer’s pathways described below, as risk factors, is highly contested. disease. A large American study (N = 3602) has also noted a APOE is accepted as an important risk factor (see above) but link between peripheral atherosclerosis and Alzheimer’s for the bulk of these genes, widely conflicting association data disease (Newman et al., 2005). A similar link has been from different populations is the norm rather than the exception observed in the Alzheimer’s disease brain where cognitive (see the Alzgene database for discussion and a full referencing decline is related to small vessel arteriosclerosis and cerebral of all positive and negative association studies (Bertram et al., amyloid angiopathy. In a neuropathological study of 137 2005)). A widely held view, given the enormous problems of autopsy confirmed Alzheimer’s disease cases, 92% showed replicability in genetic association studies, is that many (if not cerebral arteriosclerotic changes