miR‐107‐5p ameliorates neurological damage, oxidative stress, and immune responses in mice with Alzheimer's disease by suppressing the Toll‐like receptor 4 (TLR4)/nuclear factor‐kappaB(NF‐κB) pathway

Abstract

AbstractAlzheimer's disease (AD) is a progressively debilitating neurodegenerative condition primarily affecting the elderly. Emerging research suggests that microRNAs (miRNAs) play a role in the development of AD. This study investigates the impact of miR‐107‐5p on neurological damage, oxidative stress, and immune responses in AD. We utilized APP/PS1 mice as AD mouse models and C57BL/6 J mice as controls. AD mice received treatment with agomir miR‐107‐5p (to overexpress miR‐107‐5p) or BAY11‐7082 (an NF‐κB pathway inhibitor). We evaluated learning and memory abilities through the Morris water maze test. Histopathological changes, hippocampal neuron distribution, and apoptosis were assessed using hematoxylin–eosin, Nissl, and TUNEL staining. Reactive oxygen species (ROS) levels, amyloid‐Aβ (Aβ1‐40/42) contents, and inflammatory factors (TNF‐α, IL‐6, IL‐1β) in hippocampal tissues were measured using ROS kits and enzyme‐linked immunosorbent assay (ELISA). Microglial activation in hippocampal tissues was observed under a fluorescence microscope. miR‐107‐5p's binding to TLR4 was predicted via the TargetScan database and confirmed through a dual‐luciferase assay. miR‐107‐5p expression, along with TLR4, APOE, and TREM2 in hippocampal tissue homogenate, and NF‐κB p65 protein expression in the nucleus and cytoplasm were assessed via RT‐qPCR and Western blot. Overexpression of miR‐107‐5p ameliorated hippocampal neurological damage, oxidative stress, and immune responses. This was evidenced by improved enhanced learning/memory abilities, reduced Aβ1‐40 and Aβ1‐42 levels, diminished neuronal injuries, decreased ROS and TNF‐α, IL‐6, and IL‐1β levels, increased APOE and TREM2 levels, and suppressed microglial activation. miR‐107‐5p directly targeted and inhibited TLR4 expression, leading to reduced nuclear translocation of NF‐κB p65 in the NF‐κB pathway. Inhibition of the NF‐κB pathway similarly improved neurological damage, oxidative stress, and immune response in AD mice. miR‐107‐5p exerts its beneficial effects by suppressing the TLR4/NF‐κB pathway, ultimately ameliorating neurological damage, oxidative stress, and immune responses in AD mice.