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.
Department of Biochemistry and Molecular Biology, Suncoast Gerontology Center, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA.
Lars N G
LN
Nilsson
Gary W
GW
Arendash
Ralph E
RE
Leighty
David A
DA
Costa
Mark A
MA
Low
Marcos F
MF
Garcia
Jennifer R
JR
Cracciolo
Amyn
A
Rojiani
Xin
X
Wu
Kelly R
KR
Bales
Steven M
SM
Paul
Huntington
H
Potter
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