Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease

Paige E. Cramer; Renee C. Gentzel; Keith Q. Tanis; Joshua Vardigan; Yi Wang; Brett Connolly; Philip Manfre; Kenneth Lodge; John J. Renger; Celina Zerbinatti; Jason M. Uslaner

doi:10.1016/j.neurobiolaging.2017.12.011

Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease

Paige E. Cramer, Renee C. Gentzel, Keith Q. Tanis, Joshua Vardigan, Yi Wang, Brett Connolly, Philip Manfre, Kenneth Lodge, John J. Renger, Celina Zerbinatti, Jason M. Uslaner

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

40 Scopus citations

Abstract

While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.

Original language	English (US)
Pages (from-to)	92-106
Number of pages	15
Journal	Neurobiology of Aging
Volume	64
DOIs	https://doi.org/10.1016/j.neurobiolaging.2017.12.011
State	Published - Apr 2018
Externally published	Yes

Keywords

African green monkey
Alzheimer's disease
Amyloid beta
Cognition
Rhesus
Tau

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

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Cramer, P. E., Gentzel, R. C., Tanis, K. Q., Vardigan, J., Wang, Y., Connolly, B., Manfre, P., Lodge, K., Renger, J. J., Zerbinatti, C., & Uslaner, J. M. (2018). Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease. Neurobiology of Aging, 64, 92-106. https://doi.org/10.1016/j.neurobiolaging.2017.12.011

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title = "Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease",

abstract = "While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.",

keywords = "African green monkey, Alzheimer's disease, Amyloid beta, Cognition, Rhesus, Tau",

author = "Cramer, {Paige E.} and Gentzel, {Renee C.} and Tanis, {Keith Q.} and Joshua Vardigan and Yi Wang and Brett Connolly and Philip Manfre and Kenneth Lodge and Renger, {John J.} and Celina Zerbinatti and Uslaner, {Jason M.}",

note = "Funding Information: All research was funded by Merck & Co., Inc. All authors at the time of their engagement are/were employees of Merck & Co. Funding Information: The authors would like to thank Mark Forman, Sherri Motzel, and Joel Schachter for their careful review of the manuscript. The authors would also like to thank BioCare Medical for their services in conducting a portion of the immunohistochemistry. The work was sponsored by Merck & Co., Inc. Appendix A Publisher Copyright: {\textcopyright} 2017",

year = "2018",

month = apr,

doi = "10.1016/j.neurobiolaging.2017.12.011",

language = "English (US)",

volume = "64",

pages = "92--106",

journal = "Neurobiology of Aging",

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T1 - Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease

AU - Cramer, Paige E.

AU - Gentzel, Renee C.

AU - Tanis, Keith Q.

AU - Vardigan, Joshua

AU - Wang, Yi

AU - Connolly, Brett

AU - Manfre, Philip

AU - Lodge, Kenneth

AU - Renger, John J.

AU - Zerbinatti, Celina

AU - Uslaner, Jason M.

N1 - Funding Information: All research was funded by Merck & Co., Inc. All authors at the time of their engagement are/were employees of Merck & Co. Funding Information: The authors would like to thank Mark Forman, Sherri Motzel, and Joel Schachter for their careful review of the manuscript. The authors would also like to thank BioCare Medical for their services in conducting a portion of the immunohistochemistry. The work was sponsored by Merck & Co., Inc. Appendix A Publisher Copyright: © 2017

PY - 2018/4

Y1 - 2018/4

N2 - While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.

AB - While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.

KW - African green monkey

KW - Alzheimer's disease

KW - Amyloid beta

KW - Cognition

KW - Rhesus

KW - Tau

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JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease

Abstract

Keywords

ASJC Scopus subject areas

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