Background: As one of the widely used drugs for the management of type 2 diabetes mellites (T2DM), metformin is increasingly believed to delay cognitive deterioration and therapeutically for Alzheimer’s disease (AD) patients especially those with T2DM. However, studies of the potential neuroprotective effects of metformin in AD patients have reported contradictory results. Objective: This study aimed to evaluate the association between metformin and the risk of developing AD. Methods: We systematically searched the PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases to identify clinical observational studies on the relationship between AD risk and metformin use published before December 20, 2021. Two investigators independently screened records, extracted data, and assessed the quality of the studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect models. Results: After screening a total of 1,670 records, we included 10 studies involving 229,110 participants. The meta-analysis showed no significant association between AD incidence and metformin exposure (OR 1.17, 95% CI 0.88–1.56, p = 0.291). However, subgroup analysis showed that among Asians, the risk of AD was significantly higher among metformin users than those who did not (OR 1.71, 95% CI 1.24–2.37, p = 0.001). Conclusion: The available evidence does not support the idea that metformin reduces risk of AD, and it may, in fact, increase the risk in Asians. Further well-designed randomized controlled trials are required to understand the role played by metformin and other antidiabetic drugs in the prevention of AD and other neurodegenerative diseases.
Mutations in PINK1 and Parkin are a major cause of Parkinson’s disease (PD) pathogenesis. In addition, PINK1 and Parkin are two mitochondrial proteins that jointly contribute to mitochondrial homeostasis via mitophagy. Mitochondrial dysfunction is the most significant mechanism underlying PD pathogenesis. Thus, understanding the regulatory mechanism of PINK1 and Parkin expression is beneficial to the treatment of PD. In this study, we found that miR-421 expression was upregulated in mice treated with MPTP, as well as in SH-SY5Y cells treated with methyl-4-phenylpyridine (MPP+). Inhibition of miR-421 alleviated neurodegeneration in MPTP-treated mice and promoted mitophagy in MPP+-treated SH-SY5Y cells. Bioinformatics software predicted that Pink1 is a downstream target protein of miR-421. In addition, miR-421-induced Pink1 and Parkin inhibition negatively modulates mitophagy in MPP+-treated SH-SY5Y cells. In addition, our study confirmed that Pink1/Parkin is responsible for miR-421-regulated cell mitophagy. Overall, this study revealed that miR-421 regulates nerve cell mitophagy through the Pink1/Parkin pathway.
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