Aβ aggregation profiles and shifts in APP processing favor amyloidogenesis in canines

NEUROBIOLOGY OF AGING

卷:33

Article

Pop, Viorela^1,2  Head, Elizabeth^2,3,4  Berchtold, Nicole C.²  Glabe, Charles G.⁵  Studzinski, Christa M.⁶  Weidner, Adam M.⁶  Murphy, M. Paul⁶  Cotman, Carl W.^1,2,3 

[1] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA

[2] Univ Calif Irvine, Inst Memory Impairments & Neurol Dis, Irvine, CA USA

[3] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA

[4] Univ Kentucky, Sanders Brown Ctr Aging, Dept Mol & Biomed Pharmacol, Lexington, KY 40536 USA

[5] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA

[6] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY USA

关键词: Abeta star 56 kDa;    ADAM10;    APP;    Beta amyloid;    Canine;    Cingulate;    C-terminal fragments of APP;    Dog;    Insulin degrading enzyme;    Neprilysin;    Oligomer;    Secretase;    Temporal;   

DOI  :  10.1016/j.neurobiolaging.2010.02.008

来源: Elsevier

【 摘 要 】

The aged canine is a higher animal model that naturally accumulates beta-amyloid (A beta) and shows age-related cognitive decline. However, profiles of A beta accumulation in different species (40 vs. 42), its assembly states, and A beta precursor protein (APP) processing as a function of age remain unexplored. In this study, we show that A beta increases progressively with age as detected in extracellular plaques and biochemically extractable A beta 40 and A beta 42 species. Soluble oligomeric forms of the peptide, with specific increases in an A beta oligomer migrating at 56 kDa, also increase with age. Changes in APP processing could potentially explain why A beta accumulates, and we show age-related shifts toward decreased total APP protein and nonamyloidogenic (beta-secretase) processing coupled with increased amyloidogenic (beta-secretase) cleavage of APP. Importantly, we describe A beta pathology in the cingulate and temporal cortex and provide a description of oligomeric A beta 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 A beta pathogenesis. (C) 2012 Elsevier Inc. All rights reserved.

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