title: Aβ vaccination in combination with behavioral enrichment in aged beagles: effects on cognition, Aβ, and microhemorrhages.
abstract: Beta-amyloid (Aβ) immunotherapy is a promising intervention to slow Alzheimer's disease. Aging dogs naturally accumulate Aβ and show cognitive decline. An active vaccine against fibrillar Aβ 1-42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain Aβ. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in Aβ. 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 Aβ, pyroglutamate Aβ, increased cerebrospinal fluid Aβ 42 and brain-derived neurotrophic factor RNA levels but also increased microhemorrhages. ENR reduced brain Aβ and prevented microhemorrhages. The combination treatment resulted in a significant maintenance of learning over time, reduced Aβ, 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.
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
authors: Paulina R
authors: PR
authors: Davis
authors: Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors: Ginevra
authors: G
authors: Giannini
authors: Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors: Karin
authors: K
authors: Rudolph
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Nathaniel
authors: N
authors: Calloway
authors: Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors: Christopher M
authors: CM
authors: Royer
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Tina L
authors: TL
authors: Beckett
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors: M Paul
authors: MP
authors: Murphy
authors: Metacog Testing Systems, New Westminster, British Columbia, Canada.
authors: Frederick
authors: F
authors: Bresch
authors: dP and Associates, Georgetown, Ontario, Canada.
authors: Dieter
authors: D
authors: Pagani
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors: Thomas
authors: T
authors: Platt
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Xiaohong
authors: X
authors: Wang
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Amy Skinner
authors: AS
authors: Donovan
authors: Department of Physiology, University of Kentucky, Lexington, KY, USA.
authors: Tiffany L
authors: TL
authors: Sudduth
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Wenjie
authors: W
authors: Lou
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Erin
authors: E
authors: Abner
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors: Richard
authors: R
authors: Kryscio
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.
authors: Donna M
authors: DM
authors: Wilcock
authors: Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors: Edward G
authors: EG
authors: Barrett
authors: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY, USA. Electronic address: elizabeth.head@uky.edu.
authors: Elizabeth
authors: E
authors: Head
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000523:psychology*; D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000517:prevention & control*; D003071:Cognition; D015928:Cognitive Behavioral Therapy / Q000379:methods*; D004285:Dogs; D006380:Helplessness, Learned; D007167:Immunotherapy; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42)
keywords: Aging; Alzheimer's disease; Brain; Brain-derived neurotrophic factor; Canine; Cerebrovascular; Dog; Immunotherapy