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Acetyl\u2010CoA synthetase 2 (ACSS2), a nuclear\u2010localized metabolic enzyme in neurons, supports histone acetylation and learning\u2010related gene expression. We examined how ACSS2 loss affects molecular and behavioral phenotypes in a mouse model of tauopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We induced tauopathy in ACSS2 knockout and control mice via injection of pathological human tau. We assessed transcriptomic, epigenomic, and behavioral changes, and tested long\u2010term acetate supplementation as a rescue strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>ACSS2 loss worsened tau\u2010seeding\u2010related phenotypes, particularly in hippocampal pyramidal neurons and Cajal\u2013Retzius cells. Acetate supplementation rescued learning in an ACSS2\u2010dependent manner and restored gene expression linked to cognition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>ACSS2 acts as a neuroprotective metabolic enzyme in vulnerable hippocampal neurons, and targeting this pathway through dietary supplementation may offer therapeutic potential for AD and related tauopathies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>We combine tau seeding with deletion of acetyl\u2010CoA synthetase 2 (ACSS2) to test this enzyme in an Alzheimer's disease model.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Loss of ACSS2 exacerbates transcriptional and behavioral responses to tau injection.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We observe robust transcriptional dysregulation in pyramidal neurons in the hippocampus.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We observe reduced numbers of reelin\u2010producing Cajal\u2013Retzius cells in the hippocampus.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Acetate supplementation rescues transcriptional and behavioral responses to tau.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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