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Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice.
Pfitzer, Jeremiah; Pinky, Priyanka D; Perman, Savannah; Redmon, Emma; Cmelak, Luca; Suppiramaniam, Vishnu; Coric, Vladimir; Qureshi, Irfan A; Gramlich, Michael W; Reed, Miranda N.
Afiliación
  • Pfitzer J; Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.
  • Pinky PD; Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.
  • Perman S; Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.
  • Redmon E; Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.
  • Cmelak L; Department of Psychological Sciences, Auburn University, Auburn, Alabama, USA.
  • Suppiramaniam V; Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, USA.
  • Coric V; Center for Neuroscience Initiative, Auburn University, Auburn, Alabama, USA.
  • Qureshi IA; Department of Molecular and Cellular Biology, College of Science and Mathematics, Kennesaw State University, Kennesaw, Georgia, USA.
  • Gramlich MW; Biohaven Pharmaceuticals Inc., New Haven, Connecticut, USA.
  • Reed MN; Biohaven Pharmaceuticals Inc., New Haven, Connecticut, USA.
J Neurochem ; 2024 Aug 30.
Article en En | MEDLINE | ID: mdl-39214859
ABSTRACT
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-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aß) and tau-related 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 Aß models, suggesting the changes in pool size may be due to Aß 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-month-old 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-modulating drugs such as troriluzole in Alzheimer's disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Neurochem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Neurochem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido