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Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer's disease model mice independent of brain amyloid ß pathology.
Kasica, Nicole P; Zhou, Xueyan; Jester, Hannah M; Holland, Caroline E; Ryazanov, Alexey G; Forshaw, Tom E; Furdui, Cristina M; Ma, Tao.
Afiliación
  • Kasica NP; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
  • Zhou X; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
  • Jester HM; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
  • Holland CE; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
  • Ryazanov AG; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States.
  • Forshaw TE; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
  • Furdui CM; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
  • Ma T; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
Front Aging Neurosci ; 14: 959326, 2022.
Article en En | MEDLINE | ID: mdl-36158543
ABSTRACT
Maintenance of memory and synaptic plasticity depends on de novo protein synthesis, and accumulating evidence implicates a role of dysregulated mRNA translation in cognitive impairments associated with Alzheimer's disease (AD). Accumulating evidence demonstrates hyper-phosphorylation of translation factor eukaryotic elongation factor 2 (eEF2) in the hippocampi of human AD patients as well as transgenic AD model mice. Phosphorylation of eEF2 (at the Thr 56 site) by its only known kinase, eEF2K, leads to inhibition of general protein synthesis. A recent study suggests that amyloid ß (Aß)-induced neurotoxicity could be associated with an interaction between eEF2 phosphorylation and the transcription factor nuclear erythroid 2-related factor (NRF2)-mediated antioxidant response. In this brief communication, we report that global homozygous knockout of the eEF2K gene alleviates deficits of long-term recognition and spatial learning in a mouse model of AD (APP/PS1). Moreover, eEF2K knockout does not alter brainpathology in APP/PS1 mice. The hippocampal NRF2 antioxidant response in the APP/PS1 mice, measured by expression levels of nicotinamide adenine dinucleotide plus hydrogen (NADPH) quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), is ameliorated by suppression of eEF2K signaling. Together, the findings may contribute to our understanding of the molecular mechanisms underlying AD pathogenesis, indicating that suppression of eEF2K activity could be a beneficial therapeutic option for this devastating neurodegenerative disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Aging Neurosci Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Aging Neurosci Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos