{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T23:41:31Z","timestamp":1783554091597,"version":"3.55.0"},"reference-count":79,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early\u2010stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta\u2010amyloid (A\u03b2) and tau\u2010related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in A\u03b2 models, suggesting the changes in pool size may be due to A\u03b2 and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8\u2010month\u2010old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate\u2010modulating drugs such as troriluzole in Alzheimer's disease.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16215-fig-0009-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16215","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T22:38:50Z","timestamp":1725057530000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in\n                    <scp>3xTg<\/scp>\n                    \u2010\n                    <scp>AD<\/scp>\n                    mice"],"prefix":"10.1111","volume":"169","author":[{"given":"Jeremiah","family":"Pfitzer","sequence":"first","affiliation":[{"name":"Department of Drug Discovery and Development Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka D.","family":"Pinky","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savannah","family":"Perman","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Redmon","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Cmelak","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu","family":"Suppiramaniam","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development Auburn University  Auburn Alabama USA"},{"name":"Center for Neuroscience Initiative Auburn University  Auburn Alabama USA"},{"name":"Department of Molecular and Cellular Biology, College of Science and Mathematics Kennesaw State University  Kennesaw Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Coric","sequence":"additional","affiliation":[{"name":"Biohaven Pharmaceuticals Inc.  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