The close interaction and interdependence of glial cells and neurons allows for the possibility that glial dysfunction contributes to and amplifies neurodegenerative pathology. Drivers of glial cell activation may represent important targets to preserve normal homeostatic maintenance and modify disease progression. We report here that semaphorin 4D (SEMA4D) is a trigger of astrocyte activation and is upregulated in neurons under stress or damage, as characterized in brains from mouse models as well as patients with Huntington’s and Alzheimer’s disease. These SEMA4D+ neurons are in close proximity to reactive astrocytes that evidence distinctive morphologic changes and downregulation of glutamine synthetase associated with reactive astrogliosis along with loss of some key normal astrocyte functions, including glucose transport and glutamate recycling. It is further demonstrated that astrocytes express cognate plexin receptors for SEMA4D and that binding to the ligand results in collapse of the actin cytoskeleton and down regulation of glutamine synthetase, and glucose and glutamate transport. These effects are prevented and reversed in cultures of iPSC-derived human astrocytes by antibody blockade of SEMA4D. In vivo antibody neutralization of SEMA4D reduced reactive astrocyte phenotype and prevented characteristic loss of GABAergic synapses in brains of CVN mice. These results suggest that SEMA4D represents a novel driver of astrocyte transformation that is upregulated early during disease progression and that antibody blockade of SEMA4D can preserve normal astrocyte and neuronal function.