Complement C4b as a key mediator of synaptic loss and cognitive decline in brain aging

Brain aging is a major risk factor for cognitive decline and neurodegenerative diseases, driven by synaptic loss, reduced synaptic function, and inflammation. However, the molecular mechanisms underlying these dysfunctions remain unclear. Here, we conducted comparative transcriptomic analyses of brain regions (cortex and hippocampus) and kidney tissues, a peripheral organ with documented age-related dysfunction. Our study uncovered common and tissue-specific aging molecular signatures, highlighting the complexity of aging-related gene expression dynamics. Notably, we identified complement component C4b as a key mediator linking inflammation to synaptic degeneration. Experimental modulation of C4b expression in aged neurons restored synaptic integrity and neuronal activity in vitro, while in vivo CRISPR-Cas13d-mediated suppression enhanced synaptic density and improved cognitive performance in aged mice. These findings establish C4b as a critical driver of age-associated cognitive decline and a promising therapeutic target for mitigating neurodegenerative changes.