Inflammatory signaling attenuates spliceosome function and cognitive ability

Cognitive impairment is a complex condition with diverse causes, but the underlying mechanisms remain elusive. In this study, to explore whether and how inflammation affects cognitive impairment, we adopted two inflammation mouse models, coronavirus disease 2019 (COVID-19) inflammation and acute kidney injury (AKI)-induced inflammation. We observed that the inflammatory response caused accumulation of the oligomer marker derived from the short form of cleaved APP in the brain and cognitive impairment, which was associated with inflammation-induced activation of FGF2 in the mice. Notably, upon FGF2 activation, the HNRNPA1 was partially translocated from the nucleus to the cytoplasm and was degraded by macroautophagy/autophagy. Concurrently, a decrease in the nuclear HNRNPA1 levels impaired autophagy ability through downregulating ATG16L1α isoform via skipped exons in the brain of inflammation mice, thus attenuating autophagic clearance of the oligomers in the brain. The accumulation of the oligomers in the hippocampus region and cognitive impairment were also detected in FGF2-treated mice, owing to autophagy downregulation. Moreover, inhibiting FGF2 signaling via erdafitinib, an inhibitor of FGFR (fibroblast growth factor receptor) protein, partially restored autophagy and cognitive ability. Notably, autophagy ability was upregulated and the corresponding cognitive impairment were rescued in the <i>fgf2</i> knockout mice, under AKI conditions, due to retention of HNRNPA1 in the nucleus, and inhibition of the aberrant splicing of <i>ATG16L1</i>. These observations suggest that inflammation activates FGF2 signaling and attenuates autophagy, thus precipitating cognitive impairment.