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aging\u2010related learning deficits and accumulate endogenously generated non\u2010fibrillar aggregates (NFAs) of amyloid beta (A\u03b2) and amyloid precursor protein \u03b1\u2010carboxy terminal fragments.\u00a0NFA\u2010A\u03b2\u00a0correlates with synaptic loss and memory deficits more closely than does fibrillar A\u03b2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We assessed the physiological, transcriptomic, ultrastructural, histological, and metabolic changes associated with the accumulation of NFA of Dutch A\u03b2\u00a0in brains of\u00a0\n                      <jats:italic>\n                        APP\n                        <jats:sup>E693Q<\/jats:sup>\n                      <\/jats:italic>\n                      \u00a0mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Aging\u2010related accumulation of NFA\u2010A\u03b2 in\u00a0\n                      <jats:italic>\n                        APP\n                        <jats:sup>E693Q<\/jats:sup>\n                      <\/jats:italic>\n                      \u00a0mice was revealed by A11 immunohistochemistry and cyclic D,L\u2010\u03b1\u2010peptide\u2010fluorescein\u20105\u2010isothiocyanate microscopy. Presynaptic termini of\u00a0\n                      <jats:italic>\n                        APP\n                        <jats:sup>E693Q<\/jats:sup>\n                      <\/jats:italic>\n                      \u00a0mice developed physiological abnormalities in post\u2010tetanic potentiation, synaptic fatigue,\u00a0synaptic vesicle replenishment, and an aging\u2010related reduction in mitochondrial complex I activity. Single\u2010cell RNA sequencing showed that excitatory neurons exhibited an altered transcriptomic profile involving \u201cprotein translation\u201d and \u201coxidative phosphorylation.\u201d\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Accumulation of NFA\u2010A\u03b2 alters neuronal metabolism but does not activate inflammation. Depletion of all forms of A\u03b2 may be required to eliminate A\u03b2 toxicity with anti\u2010amyloid antibodies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71426","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T11:00:53Z","timestamp":1781002853000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Endogenously generated Dutch\u2010type A\u03b2 non\u2010fibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation"],"prefix":"10.1002","volume":"22","author":[{"given":"Emilie L.","family":"Castranio","sequence":"first","affiliation":[{"name":"Department of Neurology Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merina","family":"Varghese","sequence":"additional","affiliation":[{"name":"George and Anne Ryan Institute for Neuroscience, University of Rhode Island  Kingston Rhode Island USA"},{"name":"Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elentina K.","family":"Argyrousi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Department of Medicine Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuldeep","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Bar\u2010Ilan University  Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8574-4640","authenticated-orcid":false,"given":"Akiko","family":"Asada","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan University  Hachioji Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"S\u00f6derberg","sequence":"additional","affiliation":[{"name":"BioArctic  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Bresnahan","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Hematology and Oncology Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lerner","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Garretti","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Department of Medicine Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"van de Loo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Department of Medicine Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl D.","family":"Stimpson","sequence":"additional","affiliation":[{"name":"Department of Pathology Uniformed Services University of Health Sciences  Bethesda Maryland USA"},{"name":"Henry M. 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