ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system (CNS), ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells within the CNS, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in CNS lipid metabolism. Here we demonstrate that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1؊/؊ glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1؊/؊ astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains of ABCA1؊/؊ mice. Taken together, these results show that glial ABCA1 is a key influence on apoE metabolism in the CNS.

ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate ␤-amyloid (A␤) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable A␤ levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/ PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/ PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.Alzheimer disease (AD) 8 is the most common cause of senile dementia and currently affects ϳ40% of the population over 80 years of age. Clinically, AD is characterized by severe impairments in memory and executive cortical functions as well as difficulties in language, calculation, visuospatial perception, behavior, and judgment (1). Characteristic neuropathological hallmarks of AD include intraneuronal fibrillary tangles composed of hyperphosphorylated tau protein and amyloid deposits that are composed largely of A␤ peptides, apolipoprotein E (apoE), lipids, and other proteins that accumulate in the neural parenchyma and the cerebrovasculature (2, 3). A␤ peptides are a heterogeneous group of peptides 39 -43 amino acids in length that are proteolytically cleaved from amyloid precursor protein (APP) by ␥-and ␤-secretases (4, 5). A␤40 and A␤42 are the main A␤ species in the brain. A␤42 is less soluble and is present in all types of senile plaques, whereas A␤40 is the major species deposited in cerebral blood vessels (4 -7).Most affected individuals have late onset AD that typically manifests after 70 years of age. However, a number of families develop the disease in their 4th or 5th decades (8, 9). The cases of familial AD result from mutations within APP or secretase components (8, 10). For example, the Swedish mutation (K670M/N671L) increases the amount of A␤ peptide that is generated from APP (11, 12). Other APP mutations, including the Dutch (E693D) and Iowa (Q694N) mutations, alter the charge of the A␤ peptide and result in amyloid deposition predominantly in the cerebral blood vessels rather than in the parenchyma (13-16). In addition to mutations in APP, over 100 different mutations have been identified in presenilin-1 alone (17). However, less than 5% of the overall clinical burden of AD is caused by mutations in APP and presenilins combined.To date, the only well established risk factor for late-onset AD is apoE (18,19). In the hum...

These results show that ABCA1 plays an important role in lipid transport in Sertoli cells and influences male fertility. -Selva,

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Several lines of evidence suggest that dysregulated lipid metabolism may participate in the pathogenesis of Alzheimer's disease (AD). Epidemiologic studies suggest that elevated mid-life plasma cholesterol levels may be associated with an increased risk of AD and that statin use may reduce the prevalence of AD. Cellular studies have shown that the levels and distribution of intracellular cholesterol markedly affect the processing of amyloid precursor protein into A beta peptides, which are the toxic species that accumulate as amyloid plaques in the AD brain. Most importantly, genetic evidence identifies apolipoprotein E, the major cholesterol carrier in the central nervous system, as the primary genetic risk factor for sporadic AD. In humans, apoE exists as three major alleles (apoE2, apoE3, and apoE4), and inheritance of the apoE4 allele increases the risk of developing AD at an earlier age. However, exactly how apoE functions in the pathogenesis of AD remains to be fully determined. Our studies have identified that the cholesterol transporter ABCA1 is a crucial regulator of apoE levels and lipidation in the brain. Deficiency of ABCA1 leads to the loss of approximately 80% of apoE in the brain, and the residual 20% that remains is poorly lipidated. Several independent studies have shown this poorly lipidated apoE increases amyloid burden in mouse models of AD, demonstrating that apoE lipidation by ABCA1 affects key steps in amyloid deposition or clearance. Conversely, robust overexpression of ABCA1 in the brain promotes apoE lipidation and nearly eliminates the formation of mature amyloid plaques. These studies show that the lipid binding capacity of apoE is a major mechanism of its function in the pathogenesis of AD, and suggest that increasing apoE lipidation may be of therapeutic importance for this devastating disease.

Although intracellular cholesterol levels are known to influence the proteolysis of b-amyloid precursor protein (APP), the effect of specific genes that regulate cholesterol metabolism on APP processing remains poorly understood. The cholesterol transporter ABCG1 facilitates cholesterol efflux to HDL and is expressed in brain. Notably, the human ABCG1 gene maps to chromosome 21q22.3, and individuals with Down syndrome (DS) typically manifest with Alzheimer's disease (AD) neuropathology in their 30s. Here, we demonstrate that expression of ABCG1 enhances amyloid-b protein (Ab) production in transfected HEK cells in a manner that requires functional cholesterol transporter activity. ABCG1-expressing cells also exhibit increased secreted APP (sAPP)a and sAPPb secretion and display increased cell surface-associated APP. These results suggest that ABCG1 increases the availability of APP as a secretase substrate for both the amyloidogenic and nonamyloidogenic pathways. In vivo, ABCG1 mRNA levels are 2-fold more abundant in DS brain compared with age-and sex-matched normal controls. Finally, both Ab and sAPPa levels are increased in DS cortex relative to normal controls. These findings suggest that altered cholesterol metabolism and APP trafficking mediated by ABCG1 may contribute to the accelerated onset of AD neuropathology in DS.-Tansley, G.

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXRresponsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Ab production. To clarify the in vivo roles of ABCG1 in Ab metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Ab, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Ab levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Ab metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.-Burgess,

Objective-The purpose of this study was to evaluate the effects of whole body overexpression of human ABCG1 on atherosclerosis in apoE Ϫ/Ϫ mice. Methods and Results-We generated BAC transgenic mice in which human ABCG1 is expressed from endogenous regulatory signals, leading to a 3-to 7-fold increase in ABCG1 protein across various tissues. Although the ABCG1 BAC transgene rescued lung lipid accumulation in ABCG1 Ϫ/Ϫ mice, it did not affect plasma lipid levels, macrophage cholesterol efflux to HDL, atherosclerotic lesion area in apoE Ϫ/Ϫ mice, or levels of tissue cholesterol, cholesterol ester, phospholipids, or triglycerides. Subtle changes in sterol biosynthetic intermediate levels were observed in liver, with chow-fed ABCG1 BAC Tg mice showing a nonsignificant trend toward decreased levels of lathosterol, lanosterol, and desmosterol, and fat-fed mice exhibiting significantly elevated levels of each intermediate. These changes were insufficient to alter ABCA1 expression in liver. high-density lipoprotein (HDL) metabolism, reverse cholesterol transport, atherosclerosis, and cell and body sterol homeostasis. 1-3 ABCA1 catalyzes cholesterol and phospholipid efflux to lipid-free apolipoprotein A-I (apoA-I) to form pre-␤ HDL. 4 -7 Deficiency of human ABCA1 results in Tangier Disease, characterized by virtually undetectable plasma HDL, tissue deposition of cholesterol esters (CE), and increased atherosclerosis risk. 6 -8 Conversely, selective overexpression of ABCA1 in mice increases plasma HDL levels 9,10 and reduces atherosclerotic lesion progression. 11,12 Plasma HDL levels are regulated largely by liver and intestinal ABCA1. 13,14 Macrophage ABCA1 makes only a minor contribution to plasma HDL but plays a key role in atherosclerosis. 12,[15][16][17] ABCG1 is the founding member of the ABCG subclass of ABC transporters. 18 In vitro and in vivo studies have shown that ABCG1 mediates cholesterol efflux to HDL and other phospholipid-enriched but not lipid-free apolipoproteins. 19 -27 In cells, ABCG1 also redistributes cellular cholesterol to cholesterol oxidase-accessible membrane domains. 28 Both the cholesterol efflux and redistribution activities are present when ABCG1 is selectively overexpressed in cells, showing that ABCG1 functions as a homodimer. 19,26 -28 In vivo, ABCG1 is broadly expressed 20,20,26,29 and is induced by lipid loading as well as by Liver X Receptor/Retinoic Acid Receptor (LXR/RXR) agonists. 19,30 -33 Under basal conditions, liver ABCG1 is 76-fold more abundant in Kupffer cells and 27-fold more abundant in endothelial cells compared to hepatocytes. 32 A high-cholesterol diet specifically increases hepatocyte ABCG1 expression, 32 suggesting that hepatocyte ABCG1 is sensitive to regulatory pathways important for tissue lipid homeostasis. Macrophage ABCG1 is also induced by lipid loading 34 and is upregulated in macrophages isolated from individuals with Tangier Disease. 35 Conversely, cholesterol efflux from lipid-laden macrophages suppresses ABCG1 expression, 34 and antisense inhibition o...