Affiliations: [a] Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| [b] Department of Pharmacology and Neuroscience Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| [c] Department of Neurology Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| [d] Department of Speech, Language and Hearing Sciences Departments, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| [e] Department of Public Health, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| [f] Nutritional Sciences Department, Texas Tech University, Lubbock, TX, USA
Correspondence:
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Correspondence to: P. Hemachandra Reddy, PhD and Murali Vijayan, PhD, Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA. Tel.: +1 806 743 3194; E-mail: [email protected] (P. Hemachandra Reddy). Tel.: +1 806 743 2479; E-mail: [email protected] (M. Vijayan).
Abstract: Background:The intricate and complex molecular mechanisms that underlie the progression of Alzheimer’s disease (AD) have prompted a concerted and vigorous research endeavor aimed at uncovering potential avenues for therapeutic intervention. Objective:This study aims to elucidate the role of miRNA PC-5P-12969 in the pathogenesis of AD. Methods:We assessed the differential expression of miRNA PC-5P-12969 in postmortem AD brains, AD animal and cell models using real-time reverse-transcriptase RT-PCR, we also checked the gene and protein expression of GSK3α and APP. Results:Our investigation revealed a notable upregulation of miRNA PC-5P-12969 in postmortem brains of AD patients, in transgenic mouse models of AD, and in mutant APP overexpressing-HT22 cells. Additionally, our findings indicate that overexpression of miRNA PC-5P-12969 exerts a protective effect on cell survival, while concurrently mitigating apoptotic cell death. Further-more, we established a robust and specific interaction between miRNA PC-5P-12969 and GSK3α. Our luciferase reporter assays provided confirmation of the binding between miRNA PC-5P-12969 and the 3′-UTR of the GSK3α gene. Manipulation of miRNA PC-5P-12969 levels in cellular models of AD yielded noteworthy alterations in the gene and protein expression levels of both GSK3α and APP. Remarkably, the manipulation of miRNA PC-5P-12969 levels yielded significant enhancements in mitochondrial respiration and ATP production, concurrently with a reduction in mitochondrial fragmentation, thus unveiling a potential regulatory role of miRNA PC-5P-12969 in these vital cellular processes. Conclusions:In summary, this study sheds light on the crucial role of miRNA PC-5P-12969 and its direct interaction with GSK3α in the context of AD.
