| First Author | Fitz NF | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 38 | Pages | 13125-36 |
| PubMed ID | 22993429 | Mgi Jnum | J:188282 |
| Mgi Id | MGI:5440124 | Doi | 10.1523/JNEUROSCI.1937-12.2012 |
| Citation | Fitz NF, et al. (2012) Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice. J Neurosci 32(38):13125-36 |
| abstractText | 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, Abca1 deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). The APOEepsilon4 allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect of Abca1 deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1DeltaE9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examined Abca1 gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy of Abca1 significantly exacerbates memory deficits in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. The data for amyloid plaques and insoluble amyloid-beta (Abeta) also show that Abca1 hemizygosity increases Abeta deposition only in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. Our in vivo microdialysis assays indicate that Abca1 deficiency significantly decreases Abeta clearance in ApoE4-expressing mice, while the effect of Abca1 on Abeta clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and Abeta42 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 Abeta clearance. Overall, our results prove that the presence of functional Abca1 significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1-APOE regulatory axis. |
