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Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles which significantly affects people's life quality. Recently, AD has been found to be closely related to autophagy. The aim of this study was to identify autophagy-related genes associated with the pathogenesis of AD from multiple types of microarray and sequencing datasets using bioinformatics methods and to investigate their role in the pathogenesis of AD in order to identify novel strategies to prevent and treat AD. Our results showed that the autophagy-related genes were significantly downregulated in AD and correlated with the pathological progression. Furthermore, enrichment analysis showed that these autophagy-related genes were regulated by the transcription factor myocyte enhancer factor 2A (MEF2A), which had been confirmed using si-MEF2A. Moreover, the single-cell sequencing data suggested that MEF2A was highly expressed in microglia. Methylation microarray analysis showed that the methylation level of the enhancer region of MEF2A in AD was significantly increased. In conclusion, our results suggest that AD related to the increased methylation level of MEF2A enhancer reduces the expression of MEF2A and downregulates the expression of autophagy-related genes which are closely associated with AD pathogenesis, thereby inhibiting autophagy.

SUBMITTER: Li H

PROVIDER: S-EPMC8242211 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) is one of the most common types of dementia that causes memory, thinking, and behavior problems. The most important feature of AD is the gradual irreversible loss of cognitive ability through the formation of amyloid ? (A?) plaques and neurofibrillary tangles composed of tau protein. The metabolism of A? and tau proteins is closely related to and is affected by autophagy. Current research speculates that autophagy dysfunction leads to an increase in harmful proteins in AD. ?-Asarone is the main constituent of Acorus tatarinowii Schott and has important effects on the central nervous system. In this paper, we primarily explored the effects of ?-asarone on the clearance of noxious proteins and the associated potential mechanisms via autophagy in a PC12 cell AD model. A CCK-8 assay and LDH experiments were used to assess cell viability/toxicity, and SPiDER-?Gal was used to detect cellular senescence. The important proteins associated with the pathogenesis of AD including APP, PS1, A?, BACE1, and SYN1 were analyzed by immunofluorescence (IF) and Western blot analysis. Antimycin A (A3) and cyclosporine A (CSA) were selected as the activators and inhibitors of autophagy, respectively. LC3, BECN, P62, PINK1, and Parkin protein expression were also examined by IF and Western blot analysis. The data showed that ?-asarone administration significantly dose-dependently increased cell proliferation and decreased cytotoxicity; moreover, ?-asarone inhibited SA-?Gal and improved cell senescence. The results further showed that, compared to the model, APP, PS1, A?, BACE1, and p62 were reduced, while SYN1, BECN1, and LC3 were increased after treatment with ?-asarone. The results of Canonical Correlation Analysis (CCA) showed a highly significant relationship between the pathological factors of AD and the protein expression of autophagy. In conclusion, our study demonstrated that ?-asarone can inhibit A?, and this effect may occur by promoting autophagy in a cell model of AD.

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Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer's Disease.

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