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We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Mitochondrial energy metabolism was recorded using two\u2010photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Recombinant or human brain\u2010derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension,\n                      <jats:italic>de novo<\/jats:italic>\n                      NADPH synthesis. This process controls expression of low\u2010density lipoprotein receptor\u2010related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2\u2010NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient\u2010derived neurons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Upregulation of mitochondrial NADK2\u2010dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71594","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:26:05Z","timestamp":1781666765000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial NADK2\u2010dependent NADPH controls tau oligomer uptake in human neurons"],"prefix":"10.1002","volume":"22","author":[{"given":"Evelyn","family":"Pardo","sequence":"first","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Wallrabe","sequence":"additional","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"},{"name":"W.M. 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Keck Center for Cellular Imaging University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garnett","family":"Mingledorff","sequence":"additional","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammasi","family":"Periasamy","sequence":"additional","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"},{"name":"W.M. 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