miR-146a-5p Modulates Adult Hippocampal Neurogenesis Deficits Through Klf4/p-Stat3 Signaling in APP/PS1 Mice

Alzheimer's disease (AD) is the most common neurodegenerative disease, and currently, no effective treatment strategies exist for this condition. MicroRNAs (miRNAs) have emerged as promising therapeutic targets of AD. Previous studies have highlighted the significant role of miR-146a-5p in regulating adult hippocampal neurogenesis (AHN). Here, we aimed to investigate whether miR-146a-5p plays a role in the mechanisms of AD. We employed quantitative real-time PCR (qRT-PCR) to assess the expression of miR-146a-5p. Additionally, we examined the expression of Krüppel-like factor 4 (Klf4), Signal transducer and activator of transcription 3 (Stat3), and phosphorylated Stat3 (p-Stat3) using western blot analysis. Furthermore, we validated the interaction between miR-146a-5p and Klf4 using a dual-luciferase reporter assay. Immunofluorescence staining was employed to evaluate AHN. And Contextual fear conditioning discrimination learning (CFC-DL) experiment was used to detect pattern separation. Our findings in the hippocampus of APP/PS1 mice revealed upregulated levels of miR-146a-5p and p-Stat3, while Klf4 levels were downregulated. Interestingly, both miR-146a-5p antagomir and p-Stat3 inhibitor obviously rescued neurogenesis and pattern separation in APP/PS1 mice. Moreover, application of miR-146a-5p agomir reversed the protective effects of Klf4 upregulation. These findings open new avenues for protection against AD through the modulation of neurogenesis and cognitive decline via the miR-146a-5p/Klf4/p-Stat3 pathway.