RESUMO
JOURNAL/nrgr/04.03/01300535-202412000-00026/figure1/v/2024-04-08T165401Z/r/image-tiff Gamma-aminobutyric acid (GABA)ergic neurons, the most abundant inhibitory neurons in the human brain, have been found to be reduced in many neurological disorders, including Alzheimer's disease and Alzheimer's disease-related dementia. Our previous study identified the upregulation of microRNA-502-3p (miR-502-3p) and downregulation of GABA type A receptor subunit α-1 in Alzheimer's disease synapses. This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function. In vitro studies were performed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs. In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunit α-1 mRNA. Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunit α-1 gene and suppresses the luciferase activity. Furthermore, quantitative reverse transcription-polymerase chain reaction, miRNA in situ hybridization, immunoblotting, and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunit α-1 level, while suppression of miR-502-3p increased the level of GABA type A receptor subunit α-1 protein. Notably, as a result of the overexpression of miR-502-3p, cell viability was found to be reduced, and the population of necrotic cells was found to be increased. The whole cell patch-clamp analysis of human-GABA receptor A-α1/ß3/γ2L human embryonic kidney (HEK) recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function, suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function. Additionally, the levels of proteins associated with Alzheimer's disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression. The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p. We propose that micro-RNA, in particular miR-502-3p, could be a potential therapeutic target to modulate GABAergic synapse function in neurological disorders, including Alzheimer's disease and Alzheimer's disease-related dementia.
RESUMO
Alzheimer's disease (AD) is a progressive neurological disease characterized by the loss of cognitive function, confusion, and memory deficit. Accumulation of abnormal proteins, amyloid beta (Aß), and phosphorylated Tau (p-tau) forms plaques and tangles that deteriorate synapse function, resulting in neurodegeneration and cognitive decline in AD. The human brain is composed of different types of neurons and/or synapses that are functionally defective in AD. The GABAergic synapse, the most abundant inhibitory neuron in the human brain was found to be dysfunctional in AD and contributes to disrupting neurological function. This study explored the types of GABA receptors associated with neurological dysfunction and various biological and environmental factors that cause GABAergic neuron dysfunction in AD, such as Aß, p-tau, aging, sex, astrocytes, microglia, APOE, mental disorder, diet, physical activity, and sleep. Furthermore, we explored the role of microRNAs (miRNAs) in the regulation of GABAergic synapse function in neurological disorders and AD states. We also discuss the molecular mechanisms underlying GABAergic synapse dysfunction with a focus on miR-27b, miR-30a, miR-190a/b, miR-33, miR-51, miR-129-5p, miR-376-3p, miR-376c, miR-30b and miR-502-3p. The purpose of our article is to highlight the recent research on miRNAs affecting the regulation of GABAergic synapse function and factors that contribute to the progression of AD.
