Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-beta peptide levels in vivo.
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.
Hirsch-Reinshagen
Veronica
V
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Chan
Jennifer Y
JY
Wilkinson
Anna
A
Tanaka
Tracie
T
Fan
Jianjia
J
Ou
George
G
Maia
Luis F
LF
Singaraja
Roshni R
RR
Hayden
Michael R
MR
Wellington
Cheryl L
CL
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis* / Q000502:physiology*; D000367:Age Factors; D000682:Amyloid / Q000032:analysis*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001057:Apolipoproteins E; D001923:Brain Chemistry; D002531:Cerebellum / Q000737:chemistry; D002540:Cerebral Cortex / Q000737:chemistry; D022202:Chromosomes, Artificial, Bacterial; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000682:Amyloid; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D012333:RNA, Messenger