Interactions established by isoform-specific TrkB-T1 sequences govern inflammatory response and neurotoxicity in stroke

Summary Ugalde-Triviño et al. develop cell-penetrating peptides derived from neurotrophin receptor TrkB-T1 to identify isoform-specific protein interactions and demonstrate protective effects on neuroinflammation and neurotoxicity reducing brain damage in a mice model of ischemic stroke, of relevance to human therapy. Glia reactivity, neuroinflammation and excitotoxic neuronal death are central processes to ischemic stroke and neurodegenerative diseases, altogether a leading cause of death, disability, and dementia. Due to the high incidence of these pathologies and the lack of efficient treatments, it is a priority developing brain protective therapies impacting both neurons and glial cells. Truncated neurotrophin receptor TrkB-T1, a protein produced by all these cells, plays relevant roles in excitotoxicity and ischemia. We have hypothesized that interactions established by isoform-specific TrkB-T1 sequences might be relevant to neurotoxicity and/or reactive gliosis and, therefore, constitute a therapeutic target. We identify here the TrkB-T1-specific interactome, poorly described to date, and demonstrate that interference of these protein-protein interactions using brain-accessible TrkB-T1-derived peptides can prevent reactive gliosis and decrease excitotoxicity-induced damage in cellular and mouse models of stroke. The pivotal role played by TrkB-T1 on microglia and astrocyte reactivity suggests that isoform-derived peptides could become important in development of therapies for human stroke and other excitotoxicity-associated pathologies.