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Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of <jats:italic>Mapt<\/jats:italic> mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5\u00d7FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-\u03b2 plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to <jats:italic>Mapt<\/jats:italic> mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal <jats:italic>Mapt<\/jats:italic> mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5\u00d7FAD mice followed by quantification of phospho-tau aggregates and amyloid-\u03b2 plaques in their brains. Protein changes in brains of 5\u00d7FAD mice treated with the MAPT-ASO were measured by mass spectrometry.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              <jats:italic>Mapt<\/jats:italic> mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5\u00d7FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-\u03b2 plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to <jats:italic>Mapt<\/jats:italic> similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5\u00d7FAD mice, accompanied by rescue of proteome alterations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s40035-025-00499-0","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T07:36:55Z","timestamp":1753774615000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"14","author":[{"given":"Abdolhossein","family":"Zare","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeede","family":"Salehi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob M.","family":"Bader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena","family":"Wiessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Prokesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Villmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Briese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4737-2974","authenticated-orcid":false,"given":"Michael","family":"Sendtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"issue":"3 Pt 1","key":"499_CR1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1212\/WNL.42.3.631","volume":"42","author":"PV Arriagada","year":"1992","unstructured":"Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. 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