Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice

• DOI: 10.1523/jneurosci.1937-12.2012
• Publication Date: 2012-09-19T16:33:16Z
• Authors: Nicholas F. Fitz; Andrea A. Cronican; Muzamil Saleem; Abdul H. Fauq; Robert Chapman; Iliya Lefterov; Radosveta Koldamova
• Keywords: Apolipoprotein E; Tangier disease

ATP-binding cassette transporter A1 (ABCA1) regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice, Abca1 deficiency increased deposition in the brain paralleled by decreased levels Apolipoprotein E (ApoE). The APOE ε 4 allele major genetic risk factor sporadic Alzheimer's disease (AD). Here, we reveal effect on phenotype mice expressing human ApoE3 or ApoE4. We used APP/E3 APP/E4 generated crossing APP/PS1ΔE9 to APOE3- APOE4-targeted replacement examined gene dose cognition. results from two behavior tests demonstrate that lack one copy significantly exacerbates memory deficits APP/E4/Abca1 −/+ but not APP/E3/Abca1 mice. data for plaques insoluble amyloid-β (Aβ) also show hemizygosity increases Aβ only Our vivo microdialysis assays indicate decreases clearance ApoE4-expressing while ApoE3-expressing was insignificant. addition, plasma HDL Aβ42 are decreased, there a negative correlation between brain, suggesting lipoproteins may be involved clearance. Overall, our prove presence functional influences APP ApoE4 further substantiate therapeutic approaches AD based ABCA1–APOE regulatory axis.