The intracellular region of truncated neurotrophin receptor TrkB-T1 is sufficient to promote brain glial reactivity, neuroinflammation and neurotoxicity

The development of advanced therapies for stroke, spinal cord injury, and neurodegenerative diseases—primary causes of death, disability and dementia—requires a comprehensive understanding of the interplay between excitotoxicity, aberrant neurotrophic-signalling, glial reactivity, and neuroinflammation. Recent evidence has identified the truncated neurotrophin receptor TrkB-T1 as a potential master regulator of these processes. TrkB-T1 levels increase after stroke whereas the pro-survival full-length isoform (TrkB-FL) decreases. Furthermore, stroke-induced excitotoxicity triggers TrkB-T1 regulated intramembrane proteolysis (RIP), which produces TrkB-T1-ICD, a poorly characterised fragment containing the receptor intracellular domain and a few transmembrane amino acids. This study investigated whether the TrkB-T1 intracellular domain intrinsically contributes to neurotoxicity, reactive gliosis, and neuroinflammation. Our results predict that TrkB-T1 RIP generates a nuclear localization signal in TrkB-T1-ICD that might support nuclear translocation and injury-induced transcriptional regulation in neurons undergoing excitotoxicity. Using cell-penetrating peptides (CPPs), we generated a TrkB-T1-ICD mimetic peptide (Bio-LTT1 Ct ) containing the TrkB-T1 intracellular region. Bio-LTT1 Ct translocated to the nucleus of neurons and astrocytes, provoking cell death and inducing early transcriptional changes in neurons, resembling those triggered by excitotoxicity. In vivo, intranasally administrated Bio-LTT1 Ct was brain-permeable and distributed within cortical neurons and astrocytes across both hemispheres. Notably, Bio-LTT1 Ct administration was sufficient to promote TrkB isoform imbalance, glial reactivity, and acquisition of proinflammatory profiles, all considered stroke hallmarks. In conclusion, these results imply that TrkB-T1 RIP might be a central mechanism of ischaemic damage and identify the receptor’s intracellular region as sufficient to recapitulate stroke-like effects, marking this pathological mechanism as a critical target for therapy.