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Although amyloidosis and aggregation of the 42-amino acid amyloid-\u03b2 (A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  ) have long been considered pathogenic triggers for AD, clinical evidence linking high levels of A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  with normal cognition challenges this hypothesis. To resolve this conundrum on the role of A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  in regulating synaptic activity, we used an adeno-associated viral vector approach that triggers extracellular accumulation of A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  and spatial memory impairment. We show that A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  leads to an early increase in excitatory and proximal inhibitory synaptic transmission onto hippocampal CA1 pyramidal cells, and an increased expression of the glutamate transporter GLT-1 in these cells. A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  accumulation does not cause early cognitive deficits unless accompanied by an increased neuronal GLT-1 expression, suggesting this transporter is a critical mediator of A\u03b2\n                  <jats:sub>42<\/jats:sub>\n                  \u2019s effects. These findings unveil key molecular and cellular mechanisms implicated with AD pathogenesis.\n                <\/jats:p>","DOI":"10.1101\/2025.05.27.656417","type":"posted-content","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T11:20:21Z","timestamp":1748604021000},"source":"Crossref","is-referenced-by-count":1,"title":["An increased excitation and inhibition onto CA1 pyramidal cells sets the path to Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8732-2699","authenticated-orcid":false,"given":"Patrick H.","family":"Wehrle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2525-8868","authenticated-orcid":false,"given":"Travis J.","family":"Rathwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4333-4310","authenticated-orcid":false,"given":"Maurice 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quantitative histochemistry of brain","volume":"207","year":"1954","journal-title":"III. 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