Aβ vaccination in combination with behavioral enrichment in aged beagles: effects on cognition, Aβ, and microhemorrhages

NEUROBIOLOGY OF AGING

卷:49

Article

Davis, Paulina R.^1,2  Giannini, Ginevra³  Rudolph, Karin³  Calloway, Nathaniel¹  Royer, Christopher M.³  Beckett, Tina L.¹  Murphy, M. Paul^1,4  Bresch, Frederick⁵  Pagani, Dieter⁶  Platt, Thomas^1,4  Wang, Xiaohong¹  Donovan, Amy Skinner¹  Sudduth, Tiffany L.⁷  Lou, Wenjie¹  Abner, Erin¹  Kryscio, Richard¹  Wilcock, Donna M.^1,7  Barrett, Edward G.³  Head, Elizabeth^1,2 

[1] Univ Kentucky, Sanders Brown Ctr Aging, 203 Sanders Brown Bldg,800 South Limestone St, Lexington, KY 40515 USA

[2] Univ Kentucky, Dept Pharmacol & Nutr Sci, Lexington, KY USA

[3] Lovelace Resp Res Inst, Albuquerque, NM USA

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

[5] Metacog Testing Syst, New Westminster, BC, Canada

[6] DP & Associates, Georgetown, ON, Canada

[7] Univ Kentucky, Dept Physiol, Lexington, KY USA

关键词: Aging;    Alzheimer's disease;    Brain;    Brain-derived neurotrophic factor;    Dog;    Canine;    Cerebrovascular;    Immunotherapy;   

DOI  :  10.1016/j.neurobiolaging.2016.09.007

来源: Elsevier

【 摘 要 】

Beta-amyloid (A beta) immunotherapy is a promising intervention to slow Alzheimer's disease. Aging dogs naturally accumulate A beta and show cognitive decline. An active vaccine against fibrillar A beta 1-42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain A beta. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in A beta. We hypothesized cognitive outcomes could be improved by combining VAC with ENR in aged dogs. Aged dogs (11-12 years) were placed into 4 groups: (1) control/control (C/C); (2) control/VAC (C/V); (3) ENR/control (E/C); and (4) ENR/VAC (E/V) and treated for 20 months. VAC decreased brain A beta, pyroglutamate A beta, increased cerebrospinal fluid Ab 42 and brain-derived neurotrophic factor RNA levels but also increased microhemorrhages. ENR reduced brain A beta and prevented microhemorrhages. The combination treatment resulted in a significant maintenance of learning over time, reduced A beta, and increased brain-derived neurotrophic factor mRNA despite increased microhemorrhages; however, there were no benefits to memory. These results suggest that the combination of immunotherapy with behavioral enrichment leads to cognitive maintenance associated with reduced neuropathology that may benefit people with Alzheimer's disease. (C) 2016 Elsevier Inc. All rights reserved.

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