Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation.
Biochemical and genetic studies indicate that the inflammatory proteins, apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) are important in the pathogenesis of Alzheimer's disease (AD). Using several lines of multiply transgenic/knockout mice we show here that murine ApoE and human ACT separately and synergistically facilitate both diffuse A beta immunoreactive and fibrillar amyloid deposition and thus also promote cognitive impairment in aged PDAPP(V717F) mice. The degree of cognitive impairment is highly correlated with the ApoE- and ACT-dependent hippocampal amyloid burden, with PDAPP mice lacking ApoE and ACT having little amyloid and little learning disability. A analysis of young mice before the onset of amyloid formation shows that steady-state levels of monomeric A beta peptide are unchanged by ApoE or ACT. These data suggest that the process or product of amyloid formation is more critical than monomeric A beta for the neurological decline in AD, and that the risk factors ApoE and ACT participate primarily in disease processes downstream of APP processing.
Nilsson
Lars N G
LN
Department of Biochemistry and Molecular Biology, Suncoast Gerontology Center, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA.
Arendash
Gary W
GW
Leighty
Ralph E
RE
Costa
David A
DA
Low
Mark A
MA
Garcia
Marcos F
MF
Cracciolo
Jennifer R
JR
Rojiani
Amyn
A
Wu
Xin
X
Bales
Kelly R
KR
Paul
Steven M
SM
Potter
Huntington
H
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007859:Learning Disabilities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D000514:alpha 1-Antichymotrypsin / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D000514:alpha 1-Antichymotrypsin