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

Neurobiol Dis. 2009 Sep;35(3):359-67. doi: 10.1016/j.nbd.2009.05.025. Epub 2009 Jun 10.

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/Abeta 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-3beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology*
  • Amyloid / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / pathology
  • Astrocytes / physiology
  • Cell Death / drug effects
  • Entorhinal Cortex / drug effects
  • Entorhinal Cortex / pathology
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Humans
  • Male
  • Memory / drug effects
  • Memory Disorders / drug therapy
  • Memory Disorders / pathology
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects*
  • Neurons / pathology*
  • Protease Nexins
  • Receptors, Cell Surface / genetics
  • Space Perception / drug effects
  • Thiadiazoles / blood
  • Thiadiazoles / pharmacology*
  • tau Proteins / genetics

Substances

  • APP protein, human
  • Amyloid
  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • MAPT protein, human
  • NP 031112
  • Protease Nexins
  • Receptors, Cell Surface
  • Thiadiazoles
  • tau Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3