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Suppression of this wide range of pathogenic species, seeding and toxicity mechanisms, while preserving the physiological roles of tau, presents a key therapeutic goal. Identification and targeting of signaling networks that influence a broad spectrum of tau pathogenic mechanisms might prevent or reverse synaptic degeneration and modify disease outcomes. The p75 neurotrophin receptor (p75<jats:sup>NTR<\/jats:sup>) modulates such networks, including activation of multiple tau kinases, calpain and rhoA-cofilin activity. The orally bioavailable small-molecule p75<jats:sup>NTR<\/jats:sup> modulator, LM11A-31, was administered to tau<jats:sup>P301S<\/jats:sup> mice for 3\u00a0months starting at 6\u00a0months of age, when tau pathology was well established. LM11A-31 was found to reduce: excess activation of hippocampal cdk5 and JNK kinases and calpain; excess cofilin phosphorylation, tau phosphorylation, acetylation and cleavage; accumulation of multiple forms of insoluble tau aggregates and filaments; and, microglial activation. Hippocampal extracts from treated mice had substantially reduced tau seeding activity. LM11A-31 treatment also led to a reversal of pyramidal neuron dendritic spine loss, decreased loss of dendritic complexity and improvement in performance of hippocampal behaviors. These studies identify a therapeutically tractable upstream signaling module regulating a wide spectrum of basic mechanisms underlying tauopathies.<\/jats:p>","DOI":"10.1186\/s40478-020-01034-0","type":"journal-article","created":{"date-parts":[[2020,9,5]],"date-time":"2020-09-05T06:02:53Z","timestamp":1599285773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice"],"prefix":"10.1186","volume":"8","author":[{"given":"Tao","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin C.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Leng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-4886","authenticated-orcid":false,"given":"Stephen M.","family":"Massa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank M.","family":"Longo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,5]]},"reference":[{"key":"1034_CR1","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1038\/s41467-017-01575-4","volume":"8","author":"N Ait-Bouziad","year":"2017","unstructured":"Ait-Bouziad N, Lv G, Mahul-Mellier AL, Xiao S, Zorludemir G, Eliezer D, Walz T, Lashuel HA (2017) Discovery and characterization of stable and toxic Tau\/phospholipid oligomeric complexes. 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Massa and Longo are listed as inventors on patents relating to a compound in this report (LM11A-31) that is assigned to the University of North Carolina, University of California, San Francisco and the Dept. of Veterans Affairs. Drs. Massa and Longo are entitled to royalties distributed by UC and the VA per their standard agreements. Dr. Longo is a principal of, and has financial interest in PharmatrophiX, a company focused on the development of small molecule ligands for neurotrophin receptors that has licensed several of these patents.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"156"}}