DECIPHERING THE ROLES OF TAT-TRKB AND TRKB-ICD IN MICROGLIAL FUNCTION WITHIN THE ALZHEIMER’S DISEASE CONTEXT

BDNF/TrkB-FL signalling is impaired in Alzheimer’s disease (AD) due to amyloid-beta (Aβ)-mediated cleavage of TrkB-FL, generating TrkB-ICD. Initially described in neurons, TrkB-ICD is a stable fragment capable of phosphorylating nuclear and axonal proteins, thereby reshaping transcriptomic and proteomic profiles. Notably, TrkB-ICD has been detected in the neuronal secretome, suggesting its release and potential effects on neighbouring cells, including microglia - essential for brain homeostasis. To prevent TrkB-FL cleavage, we developed a novel peptide, TAT-TrkB. This study aimed to: 1) assess the in vivo effects of TAT-TrkB on microglia and 2) determine whether microglia generate TrkB-ICD or internalize neuron-derived TrkB-ICD, as well as evaluate the functional consequences of TrkB-ICD and TAT-TrkB on microglial physiology. 5xFAD mice (AD model) received intraperitoneal TAT-TrkB (25 mg/kg) or saline 5x per week for two months to evaluate microglial and inflammatory outcomes. In vitro, primary microglia cultures from neonatal C57BL/6 mice were isolated, exposed to Aβ_25–35 with or without TAT-TrkB, or to secretome from neurons overexpressing TrkB-ICD for 24h to assess: 1) Aβ and TAT-TrkB effects and 2) neuron-derived TrkB-ICD impact. In vivo, TAT-TrkB reduced Aβ aggregation without altering the overall microglial inflammatory profile. Although microglia expressed TrkB-FL, NMDA receptors, and calpains, TrkB-ICD formation was not detected and TAT-TrkB did not affect TrkB-FL levels. However, Aβ_25–35+TAT presented alterations in membrane conductance and calcium transients. Additionally, microglia internalize neuron-derived TrkB-ICD.
Overall, these findings uncover a novel neuron–microglia communication pathway involving TrkB-ICD and support TAT-TrkB as a modulator of TrkB-related mechanisms in AD.