title: Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice.
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, Abca1 deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). The APOEε4 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/PS1ΔE9 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-β (Aβ) also show that Abca1 hemizygosity increases Aβ deposition only in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. Our in vivo microdialysis assays indicate that Abca1 deficiency significantly decreases Aβ clearance in ApoE4-expressing mice, while the effect of Abca1 on 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 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.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Fitz
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Cronican
authors.forename: Muzamil
authors.initials: M
authors.lastname: Saleem
authors.forename: Abdul H
authors.initials: AH
authors.lastname: Fauq
authors.forename: Robert
authors.initials: R
authors.lastname: Chapman
authors.forename: Iliya
authors.initials: I
authors.lastname: Lefterov
authors.forename: Radosveta
authors.initials: R
authors.lastname: Koldamova
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency*; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D003213:Conditioning, Psychological / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1 / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002784:Cholesterol