Dementia-linked TDP-43 dysregulation in astrocytes impairs memory, antiviral signaling, and chemokine-mediated astrocytic-neuronal interactions.

BACKGROUND: TDP-43 pathology is linked to cognitive deficits in diverse neurodegenerative disorders, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). The effects of TDP-43 pathology in different cell types, including astrocytes, are not clear.

METHOD: In this study, we used postmortem human brain samples, extensive behavioral testing in numerous cohorts of doubly transgenic mice, gene profiling in different isolated brain regions and cells, glial-neuronal co-culture assays and physiology, and biochemical assays to identify specific signaling cascades linked to TDP-43.

RESULT: Our results show that astrocytic TDP-43 is mislocalized in postmortem human hippocampal tissue from AD cases. To assess the effects of widespread or hippocampus specific dysregulation of astrocytic TDP-43 in complementary systems, we generated three novel astrocyte specific mouse models of TDP-43 dysfunction. Consistently, these mouse models indicated that astrocytic TDP-43 dysfunction causes progressive hippocampus-dependent memory loss, but not motor deficits. Manipulation of astrocytic TDP-43 also increased hippocampal levels of interferon -inducible chemokines CXCL9 and CXCL10, and altered cell-autonomous antiviral signaling and defense against viral pathogens. Moreover, expression of CXCR3, the shared receptor for CXCL9 and CXCL10, was increased selectively in hippocampal presynaptic terminals. Acute or chronic stimulation of presynaptic CXCR3 modulated neuronal activities and presynaptic vesicles.

CONCLUSION: Overall, our findings shed new light on TDP-43 dysregulation in astrocytes and its potential contributions to disease-related impairments in cognitive and immune-related functions. We report a novel chemokine-mediated astrocytic-neuronal pathway that is likely downstream of aberrant antiviral immune signaling in astrocytes that affects presynaptic release and neuronal activities. Together, these results implicate astrocytic TDP-43 dysregulation in the pathogenesis of dementia and point to chemokine signaling and CXCR3 as potential therapeutic targets for alleviating cognitive decline.