A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling
4 affiliations
- 1Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
- 2Department of Neurology, San Francisco Veterans Affairs Health Care System, San Francisco, CA 94121, USA
- 3Department of Neurology, University of California, San Francisco, CA 94121, USA
- 4Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA
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.
Related
- Bioactive Spirulina Protein Hydrolysate Mitigates Cyclophosphamide‐Induced Physiological, Biochemical, Histopathological, and Oxidative Stress Alterations in Rats
- Adenosine-A2 Receptor Signaling in Astrocytes Mitigates Cerebral Ischemic Injury via Suppressing Glutamate-Induced Excitotoxicity
- Roflumilast mitigates cartilage degeneration in osteoarthritis by activating CFTR-mediated anti-apoptotic signaling.
- β-glucan mitigates necrotizing enterocolitis-induced long-term cognitive impairment by remodeling gut microbiota and restoring tryptophan metabolite IAA-mediated gut–brain signaling
- Melatonin mitigates bisphenol A- and MBP-induced damage in Leydig cells by alleviating oxidative stress and endoplasmic reticulum stress via inhibition of PERK signaling pathway
BibTeX
@article{yang2026smallmolecule,
title = {{A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling}},
author = {Tao Yang and Kevin C. Tran and Albert Leng and Vanessa F. Langness and Stephen M. Massa and Frank M. Longo},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15191822},
url = {https://europepmc.org/article/PMC/PMC13664222},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling
AU - Tao Yang
AU - Kevin C. Tran
AU - Albert Leng
AU - Vanessa F. Langness
AU - Stephen M. Massa
AU - Frank M. Longo
PY - 2026
DA - 2026/10/01
JO - Cells
DO - 10.3390/cells15191822
UR - https://europepmc.org/article/PMC/PMC13664222
AB - 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.
SN - 2073-4409
ER -