Alpha-1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease.
Alpha(1)-antichymotrypsin (ACT), an acute-phase inflammatory protein, is an integral component of the amyloid deposits in Alzheimer's disease (AD) and has been shown to catalyze amyloid beta-peptide polymerization in vitro. We have investigated the impact of ACT on amyloid deposition in vivo by generating transgenic GFAP-ACT-expressing mice and crossing them with the PDGF-hAPP/V717F mice, which deposit amyloid in an age-dependent manner. The number of amyloid deposits measured by Congo Red birefringence was increased in the double ACT/amyloid precursor protein (APP) transgenic mice compared with transgenic mice that only expressed APP, particularly in the hippocampus where ACT expression was highest, and the increase was preceded by elevated total amyloid beta-peptide levels at an early age. Our data demonstrate that ACT promotes amyloid deposition and provide a specific mechanism by which inflammation and the subsequent upregulation of astrocytic ACT expression in AD brain contributes to AD pathogenesis.
Nilsson
L N
LN
Suncoast Gerontology Center, Department of Biochemistry and Molecular Biology, Moffitt Cancer Center, College of Medicine, University of South Florida, Tampa, Florida 33612, USA. lnilsson@hsc.usf.edu
Bales
K R
KR
DiCarlo
G
G
Gordon
M N
MN
Morgan
D
D
Paul
S M
SM
Potter
H
H
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D003224:Congo Red; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D020197:Head Injuries, Penetrating / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary / Q000187:drug effects / Q000502:physiology; D000514:alpha 1-Antichymotrypsin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D010982:Platelet-Derived Growth Factor; D000514:alpha 1-Antichymotrypsin; D003224:Congo Red