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...

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,

BackgroundCognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of Aβ peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.ResultsTo assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1.ConclusionThese findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

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