Basic Science and Pathogenesis.

Background: Microglia play significant roles in Alzheimer's disease (AD) pathophysiology. Current evidence suggests microglia may function in both protective and degenerative capacities, which has received little clarity from transcriptionally-characterised phenotypes uncovered from transgenic pathologies alone. BIN1 - the second-most significant risk gene for the development of late-onset AD (LOAD) - is expressed at high levels in neurons, oligodendrocytes and microglia. We examined microglial BIN1 expression and function and previously demonstrated that BIN1 regulates proinflammatory and disease-associated activation responses in microglia in vitro and in vivo (PMID 35526014). However it's role in AD-specific pathologies is as yet unknown.

Method: We used a reverse-genetic approach to conditionally delete Bin1 in microglia of the PS19 mouse model of tauopathy. We used histology, biochemistry and RNAseq analyses to determine the effects of Bin1-cKO on tau pathology and microglial responses.

Result: Our data demonstrate that microglial BIN1 facilitates levels of pathologically phosphorylated tau (p-tau), specifically in female PS19 mice. RNAseq analysis identified cell -autonomous and non-autonomous effects for microglial BIN1 during tau pathogenesis in the PS19 model. Weighted gene co-expression analyses revealed complex networks of genes regulated by microglial gene expression during tau pathogenesis. We also identified gene networks correlated with levels of formic acid-soluble p-tau, irrespective of microglial Bin1 gene manipulation.

Conclusion: These gene networks offer novel insight into microglial genes involved in responses to tau pathology, and the potential impact of BIN1 as a LOAD risk gene.