{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:03:17Z","timestamp":1785420197144,"version":"3.56.0"},"posted":{"date-parts":[[2025,6,15]]},"group-title":"Neuroscience","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T00:00:00Z","timestamp":1749945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/05ewr7t48","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Philip and Sima Needleman Center for Autophagy Therapeutics and Research"},{"name":"NIH, USA","award":["P30 AG066444"],"award-info":[{"award-number":["P30 AG066444"]}]},{"name":"NIH, USA","award":["P01 AG03991"],"award-info":[{"award-number":["P01 AG03991"]}]},{"name":"NIH, USA","award":["P01 AG026276"],"award-info":[{"award-number":["P01 AG026276"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Amyloid-\u03b2 (A\u03b2) plaques with progressively increasing reactive astrocytes characterize Alzheimer\u2019s disease (AD). Reactive astrocytes are regulated by cellular and molecular mechanisms that are known to progress A\u03b2 pathology. However, the metabolic adaptation and metabolites required to fuel these molecular changes in reactive astrocytes remain unknown. Using human AD samples,\n                  <jats:italic>in vivo<\/jats:italic>\n                  amyloid mouse models, and\n                  <jats:italic>in vitro<\/jats:italic>\n                  approaches, we demonstrate that reactive astrocytes utilize glutamine to fuel anaplerosis and meet their metabolic demands, thereby progressing amyloidosis. We show that reactive astrocytes increase Na\n                  <jats:sup>+<\/jats:sup>\n                  -coupled neutral amino acid transporters for glutamine uptake that are interdependent on Na\n                  <jats:sup>+<\/jats:sup>\n                  \/K\n                  <jats:sup>+<\/jats:sup>\n                  ATPase. Furthermore, increasing brain-glutamine levels with a high-glutamine diet exacerbated reactive astrocytes, increasing A\u03b2 burden in an amyloid mouse model. We demonstrate that glutamine undergoes glutaminolysis via glutaminase-2\/glutamate dehydrogenase-1 enzymes to be incorporated into TCA metabolites for anaplerosis. Pharmacologically or genetically blocking glutaminolysis reduces reactive astrocytes and decreases A\u03b2 pathology in an amyloid mouse. Our findings reveal the first glutamine-dependent metabolic adaptation of reactive astrocytes affecting A\u03b2 pathology, which may be harnessed for AD therapeutic strategies.\n                <\/jats:p>","DOI":"10.1101\/2025.06.12.658977","type":"posted-content","created":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T23:30:20Z","timestamp":1750030220000},"source":"Crossref","is-referenced-by-count":0,"title":["\u201cGlutaminolysis Fuels Reactive Astrocytes, Exacerbating Amyloid Pathology in Alzheimer\u2019s Disease\u201d"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9056-5325","authenticated-orcid":false,"given":"Shamulailatpam Shreedarshanee","family":"Devi","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia Luella","family":"Heese","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Leray","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Saclay, ENS Paris Saclay, CNRS, PPSM, 91190 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2614-1613","authenticated-orcid":false,"given":"Gilbert","family":"Gallardo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, 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