Abstract
BACKGROUND: Elevated 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.
METHODS: The 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.
RESULTS: We 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.
CONCLUSIONS: Taken 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.
Document Type
Article
Publication Date
9-17-2020
Digital Object Identifier (DOI)
https://doi.org/10.1186/s12974-020-01938-7
Funding Information
This study was supported by National Institute on Aging Fellowship F32AG058456.
Related Content
The datasets generated and analyzed for this study are available from the corresponding author upon reasonable request.
Repository Citation
Braun, David J.; Dimayuga, Edgardo R.; Morganti, Josh M.; and Van Eldik, Linda J., "Microglial-Associated Responses to Comorbid Amyloid Pathology and Hyperhomocysteinemia in an Aged Knock-in Mouse Model of Alzheimer's Disease" (2020). Sanders-Brown Center on Aging Faculty Publications. 140.
https://uknowledge.uky.edu/sbcoa_facpub/140
Supplemental figure 1: Tissue dissection and regions of interest for analyses.
12974_2020_1938_MOESM2_ESM.docx (74 kB)
Supplemental figure 2: HHcy model validation data.
12974_2020_1938_MOESM3_ESM.xlsx (31 kB)
Full gene expression raw dataset.
12974_2020_1938_MOESM4_ESM.tiff (6421 kB)
Full gene expression graphical dataset.
Notes/Citation Information
Published in Journal of Neuroinflammation, v. 17, issue 1, article no: 274.
© The Author(s). 2020
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.