Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-β peptide levels in vivo

Veronica Hirsch-Reinshagen,Jennifer Y Chan,Anna Wilkinson,Tracie Tanaka,Jianjia Fan,George Ou,Luis F Maia,Roshni R Singaraja,Michael R Hayden,Cheryl L Wellington

doi:10.1194/jlr.m600543-jlr200

Veronica Hirsch-Reinshagen, Jennifer Y Chan + Show 8 more

Open Access

https://doi.org/10.1194/jlr.m600543-jlr200

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Abstract

ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. To test whether excess ABCA1 protects from amyloid deposition, we crossed APP/PS1 mice to ABCA1 bacterial artificial chromosome (BAC) transgenic mice. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. However, this was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Abeta, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we then compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals. Compared with APP/PS1 controls, aged ABCA1/APP/PS1 mice exhibited increased ABCA1 mRNA, but not protein, selectively in cortex. Additionally, ABCA1 mRNA levels were not increased before amyloid deposition but were induced only in the presence of extensive Abeta and amyloid levels. These data suggest that an induction of ABCA1 expression may be associated with late-stage Alzheimer's neuropathology.

Highlights

ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E and exhibit increased amyloid load
That human ABCA1 expression was considerably more robust in the liver compared with the brain suggests that the endogenous regulatory sequences present on bacterial artificial chromosome (BAC) RP11-23H03 are less efficiently recognized in brain, that BAC RP1123H03 may be missing some elements required for robust expression in cells in the central nervous system (CNS), or that ABCA1 may be expressed in a greater proportion of total cells in liver compared with brain
Consistent with the modest degree of ABCA1 overexpression in the BAC Tg mice, PBS-soluble apolipoprotein E (apoE) levels were slightly, but significantly, increased by 15% in the cortex of ABCA1 BAC Tg mice compared with wild-type controls (P 5 0.036, n > 12)

Summary

Introduction

ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. This was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Ab, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals.

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