Microglial deficiency of Alzheimer’s genetic risk factor Bin1 elicits enhanced cortical inflammatory response

This is the authors' abstract. We don't add key points for this paper.

Bridging Integrator 1 ( BIN1 ) has been identified as the second most important risk locus for developing late-onset Alzheimer’s Disease (AD), after APOE . BIN1 is an adaptor protein implicated in cell membrane dynamics and neuronal BIN1 has been linked to cellular transport mechanisms’ defects, synaptic dysfunction and tau pathology; however, the contribution of microglial BIN1 to neuroinflammation - being a hallmark of AD - remains underexplored. To address the role of microglial BIN1 in homeostasis and neuroinflammation, we performed single-nucleus RNA sequencing and further phenotypic analysis in microglia-specific Bin1 conditional knockout (Bin1cKO) mouse brains. Our findings indicate that deletion of microglial BIN1 induces alterations in microglial morphology and inflammatory profile under homeostatic conditions. Furthermore, in response to systemic inflammation, Bin1cKO microglia is sufficient to alter the expression of key genes regulating microglial proliferation and proinflammatory activation, mostly through the enhancement of the microglial interferon (IFN) type - I - mediated inflammatory response and the elevated expression of pro-inflammatory cytokines, chemokines and complement components. Finally, a comparative analysis of transcriptomic signatures between inflammation-induced Bin1cKO mouse microglia and human microglia in early Alzheimer’s disease revealed genes with similar transcriptional change trends. Altogether, our findings suggest that microglial BIN1 acts as a critical brake on inflammatory activation and provide insight into how its deficiency may shape inflammatory susceptibility in an AD-relevant context.