Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging

Danielle Beckman, Sean Ott, Kristine Donis-Cox, William G. Janssen, Eliza Bliss-Moreau, Peter H. Rudebeck, Mark G. Baxter, John H. Morrison

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

As the average age of the population continues to rise, the number of individuals affected with age-related cognitive decline and Alzheimer's disease (AD) has increased and is projected to cost more than $290 billion in the United States in 2019. Despite significant investment in research over the last decades, there is no effective treatment to prevent or delay AD progression. There is a translational gap in AD research, with promising drugs based on work in rodent models failing in clinical trials. Aging is the leading risk factor for developing AD and understanding neurobiological changes that affect synaptic integrity with aging will help clarify why the aged brain is vulnerable to AD. We describe here the development of a rhesus monkey model of AD using soluble oligomers of the amyloid beta (Aβ) peptide (AβOs). AβOs infused into the monkey brain target a specific population of spines in the prefrontal cortex, induce neuroinflammation, and increase AD biomarkers in the cerebrospinal fluid to similar levels observed in patients with AD. Importantly, AβOs lead to similar dendritic spine loss to that observed in normal aging in monkeys, but so far without detection of amyloid plaques or tau pathology. Understanding the basis of synaptic impairment is the most effective route to early intervention and prevention or postponement of age-related cognitive decline and transition to AD. These initial findings support the use of monkeys as a platform to understand age-related vulnerabilities of the primate brain and may help develop effective diseasemodifying therapies for treatment of AD and related dementias.

Original languageEnglish (US)
Pages (from-to)26239-26246
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
DOIs
StatePublished - Dec 26 2019

Keywords

  • Alzheimer's disease
  • AβOs
  • Microglia
  • Rhesus monkey
  • Synapse

ASJC Scopus subject areas

  • General

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