A reduction in nuclear levels of TDP-43 within the brain endothelium acutely results in a loss of barrier, and chronically, over several months, leads to hallmarks of FTD in the cerebral cortex, including astrogliosis and microglial activation and behavioral defects resembling a gold-standard model of FTD, based on a loss-of-function mutation in Grn. The gene discussed is GRN; the disease is frontotemporal dementia.