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A recombinant analogue of SUMO2, SBT02, was generated and assessed for brain penetration and the ability to mitigate amyloid pathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Elevated\n                      <jats:italic>SUMO2<\/jats:italic>\n                      expression prevents cognitive and synaptic impairment in a mouse model of AD amyloid pathology. Systemic administration of SBT02 resulted in high brain bioavailability and prophylactically halted the progression of AD\u2010associated deficits. SBT02 also restored cognition and synaptic function in late\u2010stage amyloid load. Mechanistically, SUMO2 and SBT02 do not alter amyloid processing or clearance and mitigate synaptotoxicity in the presence of high amyloid loads.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>SBT02 is a promising therapeutic strategy to counteract and reverse the toxic effects of A\u03b2os in AD.<\/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>\n                            Genetic overexpression of human\n                            <jats:italic>SUMO2<\/jats:italic>\n                            prevents the long\u2010term potentiation (LTP) impairments and cognitive deficits in amyloid precursor protein (APP) transgenics without affecting amyloid pathology.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A recombinant analogue of human SUMO2, termed SBT02, when administered systemically, displays high brain bioavailability and has no adverse effects at high doses.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Prophylactic treatment of APP transgenics with SBT02 prior to the development of amyloid pathology results in the prevention of synaptic and behavioral dysfunction.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>SBT02 also reverses pre\u2010existing LTP and cognitive impairments when administered to APP transgenics with advanced and severe pathology.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>SBT02 has no impact on amyloid pathology, indicating a mechanism of action on synaptic resistance to A\u03b2 toxicity.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70030","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T08:50:50Z","timestamp":1741683050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Luana","family":"Fioriti","sequence":"first","affiliation":[{"name":"Department of Neuroscience Istituto di Ricerche Farmacologiche Mario Negri, IRCCS  Milano MI 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