Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice
Open Access
- 19 September 2012
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 32 (38), 13125-13136
- https://doi.org/10.1523/jneurosci.1937-12.2012
Abstract
ATP-binding cassette transporter A1 (ABCA1) transporter regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice,Abca1deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). TheAPOEε4allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect ofAbca1deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1ΔE9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examinedAbca1gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy ofAbca1significantly exacerbates memory deficits in APP/E4/Abca1−/+but not in APP/E3/Abca1−/+mice. The data for amyloid plaques and insoluble amyloid-β (Aβ) also show thatAbca1hemizygosity increases Aβ deposition only in APP/E4/Abca1−/+but not in APP/E3/Abca1−/+mice. Ourin vivomicrodialysis assays indicate thatAbca1deficiency significantly decreases Aβ clearance in ApoE4-expressing mice, while the effect ofAbca1on Aβ clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and Aβ42 levels in APP/E4/Abca1−/+mice are significantly decreased, and there is a negative correlation between plasma HDL and amyloid plaques in brain, suggesting that plasma lipoproteins may be involved in Aβ clearance. Overall, our results prove that the presence of functionalAbca1significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1–APOE regulatory axis.This publication has 56 references indexed in Scilit:
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