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

Fitz, Nicholas F.; Cronican, Andrea A.; Saleem, Muzamil; Fauq, Abdul H.; Chapman, Robert; Lefterov, Iliya; Koldamova, Radosveta

doi:10.1523/jneurosci.1937-12.2012

Cited by 119

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

Fitz, Nicholas F., Cronican, Andrea A., Saleem, Muzamil, Fauq, Abdul H., Chapman, Robert, Lefterov, Iliya, Koldamova, Radosveta·2012·The Journal of Neuroscience

DOI 10.1523/jneurosci.1937-12.2012PMC PMC3646580

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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 APOE ε 4 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.

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Knock-out of ABCA1 provokes an accumulation of Aβ peptide in the CNS.
“knock-out of this gene provokes an accumulation of A␤ peptide in the CNS [12,13,56].”
From Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier (2015) · cites this paper as [56]
ABCA1's impact on brain cholesterol metabolism modulates the brain's amyloid burden.
“This transporter is of prime interest in AD because its impact on brain cholesterol metabolism modulates the brain's amyloid burden.”
From Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier (2015) · cites this paper as [56]

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Background
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Authors: Fitz, N. F., Cronican, A. A., Saleem, M., Fauq, A. H., Chapman, R., Lefterov, I., & Koldamova, R.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2012-09-19
Volume: 32
Issue: 38
Pages: 13125-13136
ISSN: 0270-6474
1529-2401
DOI: 10.1523/jneurosci.1937-12.2012
PMC: PMC3646580
Cited by: 119
References: 23
Language: en
Licence: creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 181 d)

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

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