The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease.
ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate beta-amyloid (Abeta) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable Abeta levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.
Hirsch-Reinshagen
Veronica
V
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada.
Maia
Luis F
LF
Burgess
Braydon L
BL
Blain
Jean-Francois
JF
Naus
Kathryn E
KE
McIsaac
Sean A
SA
Parkinson
Pamela F
PF
Chan
Jennifer Y
JY
Tansley
Gavin H
GH
Hayden
Michael R
MR
Poirier
Judes
J
Van Nostrand
William
W
Wellington
Cheryl L
CL
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics*; D000682:Amyloid / Q000737:chemistry; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003720:Densitometry; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D019791:Guanidine / Q000737:chemistry; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D053764:Presenilin-1; D019076:Transgenes
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000682:Amyloid; D001057:Apolipoproteins E; D008055:Lipids; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D002784:Cholesterol; D019791:Guanidine