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

Paulina R. Davis; Ginevra Giannini; Karin Rudolph; Nathaniel Calloway; Christopher M. Royer; Tina L. Beckett; M. Paul Murphy; Frederick Bresch; Dieter Pagani; Thomas Platt; Xiaohong Wang; Amy Skinner Donovan; Tiffany L. Sudduth; Wenjie Lou; Erin Abner; Richard Kryscio; Donna M. Wilcock; Edward G. Barrett; Elizabeth Head

doi:10.1016/j.neurobiolaging.2016.09.007

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

Paulina R. Davis
, Ginevra Giannini
, Karin Rudolph
, Nathaniel Calloway
, Christopher M. Royer
, Tina L. Beckett
, M. Paul Murphy
, Frederick Bresch
, Dieter Pagani
, Thomas Platt
, Xiaohong Wang
, Amy Skinner Donovan
, Tiffany L. Sudduth
, Wenjie Lou
, Erin Abner
, Richard Kryscio
, Donna M. Wilcock
, Edward G. Barrett
, Elizabeth Head

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English
Pages (from-to)	86-99
Number of pages	14
Journal	Neurobiology of Aging
Volume	49
DOIs	https://doi.org/10.1016/j.neurobiolaging.2016.09.007
State	Published - Jan 1 2017

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Funding

Research reported in this article was supported by National Institutes of Health , National Institute on Aging grant number R01AG032550 to Elizabeth Head. The project described was also supported by the National Center for Advancing Translational Sciences , UL1TR000117 to Paulina R. Davis. The authors thank Dr Charles Glabe, University of California at Irvine for providing the Aβ peptide. The authors also appreciate the assistance from Valerie Ward and Dylan Armes at Lovelace Respiratory Research Institute during the cognitive testing portion of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors appreciate the editorial assistance from Paula Thomason.

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Aging	R01AG032550
National Institute on Aging
National Center for Advancing Translational Sciences (NCATS)	UL1TR000117
National Center for Advancing Translational Sciences (NCATS)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Aging
Alzheimer's disease
Brain
Brain-derived neurotrophic factor
Canine
Cerebrovascular
Dog
Immunotherapy

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

Access to Document

10.1016/j.neurobiolaging.2016.09.007

Cite this

Davis, P. R., Giannini, G., Rudolph, K., Calloway, N., Royer, C. M., Beckett, T. L., Murphy, M. P., Bresch, F., Pagani, D., Platt, T., Wang, X., Donovan, A. S., Sudduth, T. L., Lou, W., Abner, E., Kryscio, R., Wilcock, D. M., Barrett, E. G., & Head, E. (2017). Aβ vaccination in combination with behavioral enrichment in aged beagles: effects on cognition, Aβ, and microhemorrhages. Neurobiology of Aging, 49, 86-99. https://doi.org/10.1016/j.neurobiolaging.2016.09.007

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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.",

keywords = "Aging, Alzheimer's disease, Brain, Brain-derived neurotrophic factor, Canine, Cerebrovascular, Dog, Immunotherapy",

author = "Davis, \{Paulina R.\} and Ginevra Giannini and Karin Rudolph and Nathaniel Calloway and Royer, \{Christopher M.\} and Beckett, \{Tina L.\} and Murphy, \{M. Paul\} and Frederick Bresch and Dieter Pagani and Thomas Platt and Xiaohong Wang and Donovan, \{Amy Skinner\} and Sudduth, \{Tiffany L.\} and Wenjie Lou and Erin Abner and Richard Kryscio and Wilcock, \{Donna M.\} and Barrett, \{Edward G.\} and Elizabeth Head",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2017",

month = jan,

day = "1",

doi = "10.1016/j.neurobiolaging.2016.09.007",

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Davis, PR, Giannini, G, Rudolph, K, Calloway, N, Royer, CM, Beckett, TL, Murphy, MP, Bresch, F, Pagani, D, Platt, T, Wang, X, Donovan, AS, Sudduth, TL, Lou, W, Abner, E, Kryscio, R, Wilcock, DM, Barrett, EG & Head, E 2017, 'Aβ vaccination in combination with behavioral enrichment in aged beagles: effects on cognition, Aβ, and microhemorrhages', Neurobiology of Aging, vol. 49, pp. 86-99. https://doi.org/10.1016/j.neurobiolaging.2016.09.007

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T2 - effects on cognition, Aβ, and microhemorrhages

AU - Davis, Paulina R.

AU - Giannini, Ginevra

AU - Rudolph, Karin

AU - Calloway, Nathaniel

AU - Royer, Christopher M.

AU - Beckett, Tina L.

AU - Murphy, M. Paul

AU - Bresch, Frederick

AU - Pagani, Dieter

AU - Platt, Thomas

AU - Wang, Xiaohong

AU - Donovan, Amy Skinner

AU - Sudduth, Tiffany L.

AU - Lou, Wenjie

AU - Abner, Erin

AU - Kryscio, Richard

AU - Wilcock, Donna M.

AU - Barrett, Edward G.

AU - Head, Elizabeth

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Aging

KW - Alzheimer's disease

KW - Brain

KW - Brain-derived neurotrophic factor

KW - Canine

KW - Cerebrovascular

KW - Dog

KW - Immunotherapy

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UR - https://www.scopus.com/pages/publications/84992409175#tab=citedBy

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M3 - Article

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AN - SCOPUS:84992409175

SN - 0197-4580

VL - 49

SP - 86

EP - 99

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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