Front Immunol. 2026 Feb 24;17:1694824. doi: 10.3389/fimmu.2026.1694824. eCollection 2026.
ABSTRACT
BACKGROUND: A number of microRNAs are implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. Particularly, miR-34a levels in the brain are increased in Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis is unknown.
METHODS: In order to investigate the role of miR-34a in AD, we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). Their cognitive function was evaluated by Morris water maze. Immunohistochemistry and immunofluorescence were used for neuropathological evaluation. Bulk RNA-seq followed by bioinformatics was used for hippocampal transcriptomics. The effect of miR-34a knockdown on expression of interferon-stimulated genes (ISG) was determined using cultured microglial cells and quantitative PCR.
RESULTS: MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble Aβ42 to Aβ40 and with increases in soluble and insoluble Aβ40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified "cellular response to type I interferon" and "type I interferon signaling pathway" as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 and primary microglia.
CONCLUSION: Our results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.
PMID:41816335 | PMC:PMC12971419 | DOI:10.3389/fimmu.2026.1694824