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Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer’s disease

Authors
  • Braun, David J.1
  • Dimayuga, Edgardo1
  • Morganti, Josh M.1, 2, 2
  • Van Eldik, Linda J.1, 2, 2
  • 1 University of Kentucky, 101 Sanders-Brown Bldg., 800 S. Limestone Street, Lexington, KY, 40536, USA , Lexington (United States)
  • 2 University of Kentucky, Lexington, KY, USA , Lexington (United States)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 17, 2020
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12974-020-01938-7
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundElevated blood homocysteine levels, termed hyperhomocysteinemia (HHcy), is a prevalent risk factor for Alzheimer’s disease (AD) in elderly populations. While dietary supplementation of B-vitamins is a generally effective method to lower homocysteine levels, there is little if any benefit to cognition. In the context of amyloid pathology, dietary-induced HHcy is known to enhance amyloid deposition and certain inflammatory responses. Little is known, however, about whether there is a more specific effect on microglia resulting from combined amyloid and HHcy pathologies.MethodsThe present study used a knock-in mouse model of amyloidosis, aged to 12 months, given 8 weeks of B-vitamin deficiency-induced HHcy to better understand how microglia are affected in this comorbidity context.ResultsWe found that HHcy-inducing diet increased amyloid plaque burden, altered the neuroinflammatory milieu, and upregulated the expression of multiple damage-associated and “homeostatic” microglial genes.ConclusionsTaken together, these data indicate complex effects of comorbid pathologies on microglial function that are not driven solely by increased amyloid burden. Given the highly dynamic nature of microglia, their central role in AD pathology, and the frequent occurrence of various comorbidities in AD patients, it is increasingly important to understand how microglia respond to mixed pathological processes.

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