{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:00:10Z","timestamp":1781082010424,"version":"3.54.1"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Tau pathology is a major feature of Alzheimer\u2019s disease (AD) and multiple other adult-onset neurodegenerative diseases. Aberrant exposure of an N-terminal phosphatase-activating domain (PAD) is characteristic of pathological tau, representing a toxic gain of function. Exposure of the PAD in pathological tau leads to dysregulation of protein phosphatase 1\/glycogen synthase kinase 3 (PP1\/ GSK3\u03b2) signaling, inhibition of fast axonal transport, synaptic dysfunction, and altered transcription, along with other pathological consequences. Previous studies showed that TNT1, an antibody against the PAD, blocked toxicity of pathogenic forms of tau.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this article, we describe a high-throughput screen for small molecules that block TNT1 binding to the PAD in an AlphaLISA screen and bind specifically to the PAD in surface plasmon resonance assays. Candidate PAD ligands (PADis) were identified, and initial biochemical and biophysical optimization produced PADis with increased affinity and selectivity. Three candidate PADis were evaluated in neuronal (rat E18 embryonic cortical neurons) and non-neuronal cells (HEK293T human embryonic kidney cells) using a nano-bioluminescence resonance energy transfer (nanoBRET) assay to assess PP1 binding and cell toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Discussion<\/jats:title>\n                    <jats:p>\n                      All three compounds prevented PP1 binding to PAD and neurite degeneration due to pathological tau in primary cultured cortical neurons. The final candidates had an IC\n                      <jats:sub>50<\/jats:sub>\n                      value between 10 and 20 nM in neurons with low cytotoxicity, CC\n                      <jats:sub>50<\/jats:sub>\n                      &amp;gt; 75 \u03bcM in primary cultured neurons, and 40\u2013100 \u03bcM in non-neuronal cells. PADi treatment of primary cultured neurons transfected with pathogenic tau restored axonal growth and prevented neurodegeneration. These studies establish a novel approach to therapeutics for Alzheimer\u2019s disease and tauopathies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1829420","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T08:19:41Z","timestamp":1781079581000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of pathogenic tau signaling via blocking of the phosphatase-activating domain by novel small molecules"],"prefix":"10.3389","volume":"17","author":[{"given":"Raghad","family":"Nowar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, UIC Retzky College of Pharmacy, University of Illinois Chicago","place":["Chicago, IL, United States"]},{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganga Reddy","family":"Velma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, R Ken Coit College of Pharmacy, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiqiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, R Ken Coit College of Pharmacy, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anam","family":"Kidwai","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendelyn","family":"Bauc","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Ackerman-Berrier","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, R Ken Coit College of Pharmacy, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory R. J.","family":"Thatcher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, R Ken Coit College of Pharmacy, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott T.","family":"Brady","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manel","family":"Ben Aissa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, UIC Retzky College of Pharmacy, University of Illinois Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.bbadis.2004.08.010","article-title":"Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases","volume":"1739","author":"Andreadis","year":"2005","journal-title":"Biochim. 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