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Emerging evidence suggests that metabolic dysregulation contributes to AD pathogenesis, yet how metabolic alterations interface with neuronal integrity remains unclear. Here, we identify dysfunction in PFKFB3-F2,6BP (fructose-2,6-bisphosphate) metabolic axis as a key feature of AD. We show that pathological Tau aggregates aberrantly sequester PFKFB3, limiting its activity and resulting in F2,6BP depletion. F2,6BP exerts protective effects through multiple convergent mechanisms: (i) direct activation of polynucleotide kinase 3\u2019-phosphatase (PNKP) to facilitate DNA strand break repair; (ii) transcriptional upregulation of the protein phosphatase 2A catalytic subunit (PP2CA) to limit Tau phosphorylation; (iii) stabilization of PFKFB3 to diminish its sequestration into aggregates; and (iv) direct inhibition of Tau aggregation. These findings establish F2,6BP as a central node linking metabolic regulation to both genomic stability and proteostasis in AD. Importantly, exogenous F2,6BP supplementation rescues multiple pathological features across diverse model systems, including induced neuronal cell lines (iN), primary neurons, organotypic hippocampal slice cultures, and in a\n                  <jats:italic>Drosophila<\/jats:italic>\n                  model of AD. These findings redefine F2,6BP as a metabolite that directly coordinates genome maintenance and proteostasis in neurons. Overall, this study identifies the PFKFB3-F2,6BP axis as a central driver of AD pathogenesis and a promising therapeutic target.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Tau aggregates sequester PFKFB3 depletes neuronal F2,6BP<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>F2,6BP links metabolism to DNA repair and Tau proteostasis<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>F2,6BP activates PNKP and upregulates PP2A to counter Tau pathology<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>F2,6BP supplementation rescues AD phenotypes across models<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.28.728580","type":"posted-content","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T21:15:12Z","timestamp":1780262112000},"source":"Crossref","is-referenced-by-count":0,"title":["A Toxic Tau-PFKFB3 Circuit Reduces F2,6BP Levels and Drives Neurodegeneration"],"prefix":"10.64898","author":[{"given":"Santi M.","family":"Mandal","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirban","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shandy","family":"Shahabi","sequence":"additional","affiliation":[{"name":"Department of 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Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Sanchez-Garcia","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Alberto Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain, and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sravan G.","family":"Sreenivasmurthy","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Zhou","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of California San Diego School of Medicine, La Jolla, CA 92093, 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