Markers of cholesterol transport are associated with amyloid deposition in the brain
ABSTRACT Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.
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ABSTRACT: The ATP-binding cassette, subfamily A, member 7 gene (ABCA7) was recently identified as a susceptible gene of Alzheimer's disease (AD) in the Caucasian population and African Americans. To test its genetic effect in the Han-Chinese population, 536 AD cases and 307 cognitive-intact, elder controls were genotyped for ABCA7 rs3764650 and apolipoprotein E (APOE) ε2/ε3/ε4 alleles. Global cognitive performance was assessed by the Mini-Mental State Examination in both AD patients and controls. For AD patients, comprehensive evaluation of each cognitive domain was further conducted as the following: (1) attention (forward and backward digit span); (2) memory (12-item word recall test); (3) executive function (category verbal fluency); (4) processing speed (Trail making test, part A); and (5) naming task (Boston naming test). ABCA7 rs3764650 was significantly associated with AD and the GG genotype carried a reduced risk for AD (odds ratio = 0.52, p = 0.0026). The association was further confirmed in 1802 population-based, healthy controls from Taiwan Biobank as a replicate (odds ratio = 0.70, p = 0.032). After adjustment of age, sex, and APOE ε4 allele, rs3764650 remained to be an independent predictor of AD (p = 0.001). The influence of ABCA7 was only evident in individuals without APOE ε4 alleles (p = 0.0004) but absent in ε4 carriers (p = 0.91). None of the cognitive tests was related to ABCA7 rs3764650 genotypes. The minor allele frequency and effect size of rs3764650 disclosed in the Han-Chinese population differed from those reported in the Caucasians and African Americans. Further studies were warranted to elucidate ABCA7's effect among different ethnic groups.Alzheimer's and Dementia 05/2014; 35(10). DOI:10.1016/j.neurobiolaging.2014.05.009 · 17.47 Impact Factor
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ABSTRACT: ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of High Density Lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer's disease (AD). A series of reports have revealed a significant impact of ABCA1 on Aβ deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.Neurobiology of Disease 05/2014; 72. DOI:10.1016/j.nbd.2014.05.007 · 5.20 Impact Factor
Article: ABCA7 in Alzheimer’s Disease[Show abstract] [Hide abstract]
ABSTRACT: ATP-binding cassette A7 (ABCA7) gene has recently been identified as a strong genetic locus associated with late-onset Alzheimer's disease (LOAD) through genome-wide association studies (GWASs). ABCA7 is a member of the ATP-binding cassette (ABC) transporter gene superfamily, which codes for 49 ABC proteins, divided into 7 subfamilies (coded A-G). As a multispan transmembrane protein, ABCA7 is most abundantly expressed in the microglial cells in the brain. The levels of ABCA7 have been detected to be increased in the Alzheimer's disease (AD) brain, which positively correlated with amyloid plaque burden and disease severity. Emerging data suggests that ABCA7 could be associated with AD via various pathways, possibly including amyloid-β (Aβ) accumulation, lipid metabolism, and phagocytosis. In this review, we summarize the known functions of ABCA7 and discuss the single-nucleotide polymorphisms (SNPs) related to LOAD, as well as their potential physiological effects. Finally, given the contributions of ABCA7 to AD pathogenesis, targeting ABCA7 might provide novel opportunities for AD therapy.Molecular Neurobiology 05/2014; 51(3). DOI:10.1007/s12035-014-8759-9 · 5.29 Impact Factor