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Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied.<\/jats:p><jats:p>SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a01.6\u00a0nM) and GSK\u20103\u03b2 (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a010.8\u00a0nM) kinase activity. Tau phosphorylation measured in cell\u2010based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC<jats:sub>50<\/jats:sub>\u00a0=\u00a016\u00a0nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose\u2010dependent reduction of transient hypothermia\u2010induced phosphorylated tau in the brains of wild\u2010type mice compared to vehicle (47%, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001). Long\u2010term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3\u00a0mg\/kg, QD, for 3\u00a0months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau\u2010positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire\u2010hang test compared to vehicle\u2010treated mice (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.048).<\/jats:p><jats:p>SM07883, a potent, orally bioavailable, brain\u2010penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.<\/jats:p>","DOI":"10.1111\/acel.13000","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T08:15:31Z","timestamp":1562141731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6972-1653","authenticated-orcid":false,"given":"Beno\u00eet","family":"Melchior","sequence":"first","affiliation":[{"name":"Samumed, LLC San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopi Kumar","family":"Mittapalli","sequence":"additional","affiliation":[{"name":"Samumed, LLC San Diego California 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