P1–053: Alzheimer's disease neuropathology is not mitigated by the physiological expression of human <i>ABCA1</i> in APP/PS1 mice

The only well–established genetic risk factor for late–onset Alzheimer's Disease (AD) is apolipoprotein E (apoE). ApoE is thought to bind Aβ peptides and to participate in the conversion of soluble Aβ into amyloid. Because apoE is required for amyloid deposition, factors that influence apoE levels may play important roles in AD pathogenesis. The cholesterol and phospholipid transporter ABCA1 is required to maintain normal brain apoE levels. The absence of ABCA1 results in up to 80% reduction in brain apoE levels, and the apoE that remains is poorly lipidated. Despite this reduction in brain apoE levels, ABCA1–deficient mice develop at least as much amyloid as ABCA1–expressing mice when crossed to animal models of AD, suggesting that ABCA1–mediated lipidation of apoE is also critical for amyloidogenesis. However, the effects of ABCA1 overexpression remain unknown. To test whether ABCA1 overexpression affects brain apoE metabolism and AD neuropathology. We determined whether the expression of a human ABCA1 transgene with its endogenous regulatory elements affected apoE levels, amyloid burden, and Aβ levels in transgenic animals. In the absence of APP and PS1 transgenes, ABCA1 BAC Tg animals exhibit a significant 15% (p<0.05) increase in apoE levels in cortex compared to wild–type controls, although no differences in cerebrospinal fluid apoE levels or cholesterol content are observed. However, when crossed to APP/PS1 mice, no differences were seen in cortical apoE levels, amyloid burden or guanidine–extractable Aβ40 or Aβ42 levels in APP/PS1 mice containing the human ABCA1 BAC transgene compared to APP/PS1 littermate controls. Analysis of human and murine ABCA1 expression demonstrated that, in the absence of APP/PS1 transgenes, ABCA1 BAC transgenic mice exhibit a two–fold increase in total ABCA1 protein levels in cortex compared to wild–type controls. However, this elevated ABCA1 protein expression is ablated in the presence of the APP/PS1 transgenes, despite maintenance of high levels of both murine and human ABCA1 mRNA. These results suggest that physiological expression of transgenic human ABCA1 does not prevent amyloid deposition in vivo, which may be due to posttranscriptional regulatory mechanisms that downregulate ABCA1 expression in the presence of AD neuropathology.

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