Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model o
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(2020) 17:274
RESEARCH
Open Access
Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer’s disease David J. Braun1*, Edgardo Dimayuga1, Josh M. Morganti1,2,3 and Linda J. Van Eldik1,2,3*
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 Bvitamin 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. Keywords: Alzheimer’s disease, Amyloid, Homocysteine, Hyperhomocysteinemia, Microglia, Neuroinflammation
Background Homocysteine (Hcy) is an intermediary in essential cellular pathways, and its metabolism depends on several vitamin cofactors, primarily B6, B9 (folic acid), and B12. Deficiencies in one or more of these are therefore a common cause of elevated blood homocysteine, termed hyperhomocysteinemia (HHcy) [1]. Evidence indicates that both elevated homocysteine itself, and the broader * Correspondence: [email protected]; [email protected] 1 Sanders-Brown Center on Aging, University of Kentucky, 101 Sanders-Brown Bldg., 800 S. Limestone Street, Lexington, KY 40536, USA Full list of author information is available at the end of the article
metabolic dysfunctions resulting from B-vitamin deficiency, are relevant to its status as a vascular risk factor and risk factor for Alzheimer’s disease (AD) [2–4]. The normal human range for Hcy in plasma is generally considered to be less than 15 μM, with increasing levels categorized as moderate (15–30 μM), intermediate (30– 100 μM), or severe (> 100 μM) HHcy. Although the prevalence of HHcy in the general population is estimated to be around 5%, it is significantly higher in the elderly [5], a population in which B-vitamin status is a major contributor to HHcy [6]. Interestingly, elderl
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