{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:35Z","timestamp":1792789295249,"version":"4.5.0"},"reference-count":141,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scully Initiative"},{"name":"Taube Family Foundation"},{"name":"Jean Perkins Foundation","id":[{"id":"https:\/\/ror.org\/04xr3ec97","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04xr3ec97","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Pathogenic amyloid-beta and tau oligomers (oA\u03b2, oTau) drive synaptic degeneration and cognitive decline in Alzheimer\u2019s 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 oA\u03b2 or oTau. Methods: Cultured hippocampal neurons were treated with oA\u03b2 or oTau \u00b1 PTX-BD4-3. Effects on synaptic proteins (\u00b1TrkB-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 oA\u03b2-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.<\/jats:p>","DOI":"10.3390\/cells15191822","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:34:25Z","timestamp":1791448465000},"page":"1822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Small-Molecule TrkB Agonist Promotes Synaptic Resilience Against A\u03b2 and Tau Oligomers and Mitigates Alterations in TrkB-Akt and Fyn Signaling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-3440","authenticated-orcid":false,"given":"Tao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Kevin C.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Albert","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3140-3008","authenticated-orcid":false,"given":"Vanessa F.","family":"Langness","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-4886","authenticated-orcid":false,"given":"Stephen M.","family":"Massa","sequence":"additional","affiliation":[{"name":"Department of Neurology, San Francisco Veterans Affairs Health Care System, San Francisco, CA 94121, USA"},{"name":"Department of Neurology, University of California, San Francisco, CA 94121, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9514-7325","authenticated-orcid":false,"given":"Frank M.","family":"Longo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA"},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Simmons, D.A., Yang, T., Massa, S.M., and Longo, F.M. 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