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Circulating metabolomics profiling reveals novel pathways associated with cognitive decline in patients with hypertension.

ABSTRACT: Background:Hypertension is a significant risk factor for cardiovascular disease, and it is associated with dementia, including Alzheimer's disease (AD). Although it may be correlated with AD in terms of symptoms, the link between hypertension and AD pathological biomarkers, and the potential underlying mechanism of hypertension with cognitive decline, are still not well understood. Methods:The Mini-Mental State Examination (MMSE) scores were used to evaluate cognitive function. Enzyme-linked immunosorbent assays were used to examine plasma amyloid-beta (A?)40, A?42, and tau concentration in hypertensive patients. Metabolomics and metagenomics were performed to identify the significantly changed circulating metabolites and microbiota between healthy individuals and hypertensive patients. Pearson's correlation was used to examine the association between cognitive indicators and differential metabolites. Results:We found significantly decreased MMSE scores, elevated plasma A?40, and decreased A?42/A?40 ratio in hypertensive patients, which are critically associated with AD pathology. Based on metabolomics, we found that significantly altered metabolites in the plasma of hypertensive patients were enriched in the benzoate degradation and phenylpropanoid biosynthesis pathways, and they were also correlated with changes in MMSE scores and A?42/A?40 ratio. In addition, metabolomics signaling pathway analysis suggested that microbial metabolism was altered in hypertensive patients. We also identified altered blood microbiota in hypertensive patients compared with the controls. Conclusions:Our study provides a novel metabolic and microbial mechanism, which may underlie the cognitive impairment in hypertensive patients.

SUBMITTER: Huang Y

PROVIDER: S-EPMC7476355 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Circulating metabolomics profiling reveals novel pathways associated with cognitive decline in patients with hypertension.

Huang Yuli Y Zheng Haoxiao H Tan Kuan K Sun Xiangdong X Ye Jinshao J Zhang Yunlong Y

Therapeutic advances in neurological disorders 20200903

<h4>Background</h4>Hypertension is a significant risk factor for cardiovascular disease, and it is associated with dementia, including Alzheimer's disease (AD). Although it may be correlated with AD in terms of symptoms, the link between hypertension and AD pathological biomarkers, and the potential underlying mechanism of hypertension with cognitive decline, are still not well understood.<h4>Methods</h4>The Mini-Mental State Examination (MMSE) scores were used to evaluate cognitive function. En ...[more]

PMID: 32952614

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Project description:Microglia, the resident immune cells of the brain, can exhibit a broad range of activation phenotypes, many of which have been implicated in several diseases and disorders of the central nervous system including those related to alcohol abuse. Given the complexity of global-scale molecular changes that define microglial activation, accurate phenotypic classification in the context of alcohol exposure is still lacking. We employed an optimized method for deep, quantitative proteome profiling of primary microglia in order to characterize their response to acute exposure to alcohol (ethanol) as well as the pro-inflammatory driver and TLR4 agonist, LPS. From this analysis, 5,062 total proteins were identified where 4,857 and 4,928 of those proteins were quantifiable by label-free quantitation in ethanol and LPS treatment groups, respectively. This study highlights the subtle, yet significant proteomic changes that occur in ethanol-treated microglia, which do not align with the robust pro-inflammatory phenotype induced by TLR4 activation. Specifically, our results indicate inhibition of several upstream regulators associated with inflammation, opposing effects on pathways such as phagocytosis upon comparison to TLR4-mediated pro-inflammatory phenotype, and a potential metabolic shift associated with increased expression of proteins related to OXPHOS and lipid homeostasis. Data are available via ProteomeXchange with identifier PXD14466. SIGNIFICANCE: Alcohol abuse has a significant impact on the central nervous system, which includes the pathophysiological mechanisms resulting from glial cell activation. Microglia, in particular, are the resident immune cells of the brain and exhibit a broad range of activation phenotypes. The molecular changes that drive microglial activation phenotype are complex and have yet to be fully characterized in the context of alcohol exposure. Our study highlights the first and most comprehensive characterization of alcohol-induced proteomic changes in primary microglia to date and has shed light on novel immune-related and metabolic pathways that are altered due to alcohol exposure. The results from this study provide an important foundation for future work aimed to understand the complexity of alcohol-induced microglial activation in vivo and other translational models of acute and chronic alcohol exposure.

Dataset Information

Circulating metabolomics profiling reveals novel pathways associated with cognitive decline in patients with hypertension.

Publications

Circulating metabolomics profiling reveals novel pathways associated with cognitive decline in patients with hypertension.

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