A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo

L. Serenó, M. Coma, M. Rodríguez, P. Sánchez-Ferrer, M. B. Sánchez, I. Gich, J. M. Agulló, M. Pérez, J. Avila, C. Guardia-Laguarta, J. Clarimón, A. Lleó, T. Gómez-Isla

Research output: Contribution to journalArticleResearchpeer-review

249 Citations (Scopus)

Abstract

Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Aβ production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3β inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD. © 2009 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)359-367
JournalNeurobiology of Disease
Volume35
Issue number3
DOIs
Publication statusPublished - 1 Sep 2009

Keywords

  • Alzheimer's disease
  • Amyloid
  • GSK-3
  • Neuronal cell death
  • Tau
  • Transgenic mice

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