Tau load and ICAM1 symbiosis dictated astrocytic reactivity and heterogeneity in progressive supranuclear palsy patients’ brains

Recent studies have consistently highlighted tau load and glia-mediated neuroinflammation as key drivers of Progressive supranuclear palsy (PSP) pathology. The neuroinflammatory axis is primarily dominated by astrocyte and microglia, both of which undergo disease-specific, dynamic transitions into reactive subtypes or activation state in response to tau pathology. However, how tau contributes to astrocyte reactivity, specifically, across PSP-affected brain layers and regions and which factors promote astrocyte-microglia neuroinflammatory crosstalk remains much-sought-after yet largely untouched domain. Here, we comprehensively explored these knowledge gaps by investigating neuronal and glial-tau load patterns and their impact on astrocyte reactivity (morphology, cellular processes and heterogeneity) and neuroinflammatory pathways across early to late PSP-affected brain regions. We performed extensive multi-marker co-immunostaining together with Golgi-Cox impregnation method on brain tissue samples from PSP and control (CN) cases and applied advanced microscopy and morphometric analyses tools to investigate brain-wide astrocytic reactivity and cortical layer heterogeneity. We observed prominent upregulation of glial P-tau load across all PSP regions relative to neuronal P-tau, with marked effect on neuronal viability and astrocytic reactivity. Notably, P-tau load elicited a dual astrocytic reactivity response characterized by reactive astrocytes and clasmatodendrosis. Reactive astrocytes exhibited increased expression of cell-adhesion molecule ICAM1, which interacted with microglia across PSP brain regions. Interestingly, ICAM1 shaped astrocytic response within PSP brain layers and regions and considerably affected blood-vessel architecture and astrocytic end-feet coverage, together with P-tau. Collectively, these findings indicate a versatile role of ICAM1 in dictating astrocytic reactivity and in promoting or sustaining neuroinflammation alongside P-tau in PSP brains.