Aβ aggregation profiles and shifts in APP processing favor amyloidogenesis in canines.
The aged canine is a higher animal model that naturally accumulates β-amyloid (Aβ) and shows age-related cognitive decline. However, profiles of Aβ accumulation in different species (40 vs. 42), its assembly states, and Aβ precursor protein (APP) processing as a function of age remain unexplored. In this study, we show that Aβ increases progressively with age as detected in extracellular plaques and biochemically extractable Aβ40 and Aβ42 species. Soluble oligomeric forms of the peptide, with specific increases in an Aβ oligomer migrating at 56 kDa, also increase with age. Changes in APP processing could potentially explain why Aβ accumulates, and we show age-related shifts toward decreased total APP protein and nonamyloidogenic (α-secretase) processing coupled with increased amyloidogenic (β-secretase) cleavage of APP. Importantly, we describe Aβ pathology in the cingulate and temporal cortex and provide a description of oligomeric Aβ across the canine lifespan. Our findings are in line with observations in the human brain, suggesting that canines are a valuable higher animal model for the study of Aβ pathogenesis.
Pop
Viorela
V
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States. vpop@llu.edu
Head
Elizabeth
E
Berchtold
Nicole C
NC
Glabe
Charles G
CG
Studzinski
Christa M
CM
Weidner
Adam M
AM
Murphy
M Paul
MP
Cotman
Carl W
CW
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D058225:Plaque, Amyloid / Q000209:etiology / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases