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.
Highlights
Elevated blood homocysteine levels, termed hyperhomocysteinemia (HHcy), is a prevalent risk factor for Alzheimer’s disease (AD) in elderly populations
Braun et al Journal of Neuroinflammation (2020) 17:274 homocysteine compared to women [7], while AD is more common in women [8], highlighting that HHcy is only one in a complex array of factors influencing any given individual’s risk of dementia
We found that elevation of homocysteine level in the context of amyloid pathology enhances parenchymal plaque deposition, subtly alters the neuroinflammatory milieu, and influences a number of genes important to microglial functioning
Summary
Elevated blood homocysteine levels, termed hyperhomocysteinemia (HHcy), is a prevalent risk factor for Alzheimer’s disease (AD) in elderly populations. Deficiencies in one or more of these are a common cause of elevated blood homocysteine, termed hyperhomocysteinemia (HHcy) [1]. Evidence indicates that both elevated homocysteine itself, and the broader. The population attributable risk of dementia from raised Hcy is estimated to be between 4 and 31%; in other words, preventing HHcy could prevent somewhere between 1 in 25 to 1 in 3 cases of AD [9]. In the USA alone, even the conservative estimate would translate to hundreds of thousands of people It follows, that reduction of HHcy in the population is an attractive goal. Correcting the acute metabolic dysfunctions underlying elevated Hcy appears to be a necessary but insufficient step to abrogate the full contribution of this risk factor to ADassociated cognitive decline [9], and adjunct treatments will likely be important moving forward
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