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Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice.
J Neurosci. 2012 Sep 19; 32(38):13125-36.JN

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+Show Affiliations

Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22993429

Citation

Fitz, Nicholas F., et al. "Abca1 Deficiency Affects Alzheimer's Disease-like Phenotype in Human ApoE4 but Not in ApoE3-targeted Replacement Mice." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 32, no. 38, 2012, pp. 13125-36.
Fitz NF, Cronican AA, Saleem M, et al. Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci. 2012;32(38):13125-36.
Fitz, N. F., Cronican, A. A., Saleem, M., Fauq, A. H., Chapman, R., Lefterov, I., & Koldamova, R. (2012). Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 32(38), 13125-36.
Fitz NF, et al. Abca1 Deficiency Affects Alzheimer's Disease-like Phenotype in Human ApoE4 but Not in ApoE3-targeted Replacement Mice. J Neurosci. 2012 Sep 19;32(38):13125-36. PubMed PMID: 22993429.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. AU - Fitz,Nicholas F, AU - Cronican,Andrea A, AU - Saleem,Muzamil, AU - Fauq,Abdul H, AU - Chapman,Robert, AU - Lefterov,Iliya, AU - Koldamova,Radosveta, PY - 2012/9/21/entrez PY - 2012/9/21/pubmed PY - 2012/12/10/medline SP - 13125 EP - 36 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 32 IS - 38 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/22993429/Abca1_deficiency_affects_Alzheimer's_disease_like_phenotype_in_human_ApoE4_but_not_in_ApoE3_targeted_replacement_mice_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=22993429 DB - PRIME DP - Unbound Medicine ER -