{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA",
    "Department of Neurology, San Francisco Veterans Affairs Health Care System, San Francisco, CA 94121, USA",
    "Department of Neurology, University of California, San Francisco, CA 94121, USA",
    "Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tao Yang",
      "orcid": "0000-0002-7698-3440"
    },
    {
      "affs": [
        0
      ],
      "name": "Kevin C. Tran"
    },
    {
      "affs": [
        0
      ],
      "name": "Albert Leng"
    },
    {
      "affs": [
        0
      ],
      "name": "Vanessa F. Langness",
      "orcid": "0000-0003-3140-3008"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Stephen M. Massa",
      "orcid": "0000-0003-0474-4886"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Frank M. Longo",
      "orcid": "0000-0002-9514-7325"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fd8w2q2jwnjv1.bib",
  "cited_by": 0,
  "doi": "10.3390/cells15191822",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664222/?tool=EBI",
  "id": "fd8w2q2jwnjv1",
  "issns": [
    "2073-4409"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13664222",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7220927963",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664222/pdf/?tool=EBI",
  "pmcid": "PMC13664222",
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/fd8w2q2jwnjv1.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:35Z",
      "native_id": "PMC:PMC13664222",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13664222"
    },
    {
      "first_seen": "2026-10-30T12:19:02Z",
      "native_id": "10.3390/cells15191822",
      "source": "crossref",
      "url": "https://www.mdpi.com/2073-4409/15/19/1822"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling",
  "title_text": "A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against Aβ and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:02Z",
  "url": "https://research.draconitic.com/paper/fd8w2q2jwnjv1",
  "venue": "Cells",
  "versions": []
}