A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling

Abstract

Highlights What are the main findings? In vitro, PTX-BD4-3 protected against oAβ-induced synaptic protein loss and elevation of Fyn, NR2B, and tau phosphorylation. Preservation of synaptic proteins following oAβ exposure was TrkB-dependent. PTX-BD4-3 also protected against oTau-induced dendritic spine loss. In APPL/S mice, PTX-BD4-3 preserved synaptic proteins and dendritic spines, improved Y-maze performance, and was associated with increased TrkB–Akt and reduced Fyn–tau signaling. What are the implications of the main findings? TrkB partial agonism may enhance synaptic resilience against oAβ- and oTau-associated neurodegeneration. These findings support further investigation of PTX-BD4-3 and TrkB partial agonism as potential therapeutic strategies for preserving synaptic function in Alzheimer’s disease. Abstract Background: Pathogenic amyloid-beta and tau oligomers (oAβ, oTau) drive synaptic degeneration and cognitive decline in Alzheimer’s disease (AD). Tropomyosin receptor kinase B (TrkB), expressed in neurons and glia, supports synaptic integrity in AD-affected regions. We tested whether PTX-BD4-3, a small-molecule TrkB partial agonist, promotes neuroprotective signaling, reduces degenerative signaling, and prevents synaptic loss in an AD mouse model and hippocampal neurons exposed to oAβ or oTau. Methods: Cultured hippocampal neurons were treated with oAβ or oTau ± PTX-BD4-3. Effects on synaptic proteins (±TrkB-blocking antibody), spine density, and Fyn, NR2B, and tau phosphorylation as well as tau oligomerization were assessed. Two cohorts of APPL/S mice, 5 and 12 months of age, received intraperitoneal PTX-BD4-3 or vehicle for 3 months, followed by assessment of synaptic proteins, dendritic spines, TrkB signaling, and Y-maze analysis. Results: In vitro, PTX-BD4-3 prevented oAβ-induced synaptic marker loss in a TrkB-dependent manner, reduced phosphorylation of Fyn, NR2B, and tau, suppressed oligomeric tau formation, and attenuated oTau-induced spine loss. In APPL/S mice, PTX-BD4-3 mitigated deficient TrkB/Akt signaling, reduced phosphorylation of Fyn and tau, preserved synaptic markers and dendritic spines, and improved Y-maze performance. Conclusions: Small-molecule TrkB partial agonists may normalize TrkB signaling and promote synaptic resilience, supporting their potential as AD therapeutics.