A comprehensive molecular study of hsa-miR-۱۴۰-۵p and hsa-miR-۳۱-۵p and their target genes MMP۹, TNF-α, TGFB۱, and SCN۲A in patients with comorbid Alzheimer’s disease and epilepsy

Objective(s): Alzheimer’s disease (AD) and epilepsy show significant bidirectional clinical comorbidity, yet their shared peripheral molecular mechanisms remain poorly characterized. This study investigated potential dysregulation of hsa-miR-۱۴۰-۵p and hsa-miR-۳۱-۵p, along with their target genes (MMP۹, TNF-α, TGFB۱, SCN۲A), in patients with comorbid AD and epilepsy.Materials and Methods: A multi-tiered study was conducted, combining a systematic bioinformatic meta-analysis of five public GEO datasets (over ۵۰۰ samples) with experimental validation using qRT-PCR in peripheral blood mononuclear cells (PBMCs) and MALDI-TOF mass spectrometry in plasma from ۲۰ comorbid patients and ۲۰ age- and sex-matched healthy controls.Results: Bioinformatic screening identified a prominent inflammatory network. Experimental validation revealed significant up-regulation of MMP۹ (۳.۹۲-fold, P<۰.۰۰۰۱) and TNF-α (۲.۲۱-fold, P=۰.۰۲۳) in comorbid patients. Conversely, hsa-miR-۱۴۰-۵p, a predicted repressor of MMP۹, was significantly down-regulated (۰.۴۵-fold, P=۰.۰۰۸), demonstrating a strong inverse correlation with MMP۹. Paradoxically, hsa-miR-۳۱-۵p was significantly up-regulated (۲.۸-fold, P<۰.۰۰۱). Changes in TGFB۱ and SCN۲A expression were not statistically significant. Proteomic profiling via MALDI-TOF identified ۵۷ differentially abundant peptide peaks, confirming exclusive detection of Aβ۱-۴۲, the loss of neurogranin-derived peptides (absent in patients), and elevated MMP۹ proteolytic fragments in the patient group.Conclusion: These preliminary findings indicate a shared peripheral molecular signature involving hsa-miR-۱۴۰-۵p, hsa-miR-۳۱-۵p, MMP۹, and TNF-α. This highlights neuroinflammatory pathways as shared features of comorbid AD and epilepsy, warranting further evaluation in larger longitudinal cohorts.

کلیدواژه ها:

Alzheimer disease ، Comorbidity ، Epilepsy ، Matrix metalloproteinase ، microRNAs ، Neuroinflammation ، Tumor necrosis factor-alpha