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Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Individuals with DS exhibit a very early onset of AD neuropathology, byt heir mid to late 30's. Extra copies of the genes on chromosome 21 may play an important role in this accelerated onset of AD in DS individuals. The amyloid precursor protein (APP) is located on chromosome 21, and among its cleavage products is amyloid-beta (Aß), a component of amyloid plaques. The presence of Aß and amyloid in the brain is a key pathogenic factor, and is considered the central and causative neuropathology in AD by the amyloid cascade hypothesis. Growing evidence suggests an important role for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromsome 21, and is believed to participate in the maintenance of cholesterol homeostasis. The effects of ABCG1 expression on the production of Aß have proved inconclusive in in vitro studies, demanding an in vivo resolution where appropriate physiology is maintained. To test the hypothesis that overexpression of ABCG1 will accelerate the onset or progression of AD in vivo, we evaluated the cognitive performance of ABCG1-overexpressing mice before and after crossing to the PDAPP mouse model of AD. Both normal and AD mice overexpressing ABCG1 showed no significant deficits on several cognitive tests, including reference and working memory task variations of the Morris Water Maze. Golgi analysis of neuronal structure revealed significantly reduced dendritic complexity in both normal and PDAPP mice overexpressing ABCG1, suggesting that the cholesterol-related functions of ABCG1 have a potentially important role in dendrite development. Interestingly, behavioural analysis of ABCG1-deficient mice revealed a gene-dose dependent trend toward worsened performance on the water maze probe trial, suggesting that the pathways that may compensate for ABCG1 overexpression could be unable to offset a complete deficiency. These experiments suggest an important role for ABCG1 in maintaining cellular cholesterol homeostasis, but do not support the hypothesis that ABCG 1 expression contributes to the accelerated onset of AD pathology in DS individuals.

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