MiR-7a-Klf4 axis as a regulator and therapeutic target of neuroinflammation and ferroptosis in Alzheimer's disease

Neuroinflammation and ferroptosis significantly contribute to neuronal death in Alzheimers disease (AD) and other neurodegenerative disorders. MicroRNAs (miRNAs) are crucial regulators of these pathological processes. We employed transcriptomic analysis in an APP/PSEN1 Tg AD mouse model to identify dysregulated miRNAs and construct a miRNA-mRNA-pathway network. We discovered increased miR7a expression in the AD brain, targeting Kruppel-like factor 4 (Klf4), a transcriptional factor implicated in A{beta} oligomer-induced neuroinflammation and RSL3-induced neuronal ferroptosis. Elevated Klf4 levels in AD mice brains suggest its involvement in AD pathology. The miR-7a mediated silencing of Klf4 alleviates neuroinflammation by modulating NF-{kappa}B, iNOS, and NLRP3 pathways, and inhibition of ferroptosis by targeting labile iron levels, GPX4, Nrf2 pathway, and mitochondrial damage. These findings highlight the neuroprotective role of miR-7a and its potential as RNA therapeutic. Pharmacological targeting of the miR-7a-Klf4 axis with blood-brain-barrier (BBB)-permeable compound effectively mitigates neuroinflammation and ferroptosis, suggesting the miR-7a-Klf4 axis as a novel therapeutic target for AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/644978v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@804f96org.highwire.dtl.DTLVardef@1e91bc7org.highwire.dtl.DTLVardef@11ed0daorg.highwire.dtl.DTLVardef@21d02e_HPS_FORMAT_FIGEXP M_FIG C_FIG