GSK-3 is essential in the pathogenesis of Alzheimer's disease

J Alzheimers Dis. 2006;9(3 Suppl):309-17. doi: 10.3233/jad-2006-9s335.

Abstract

Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3beta is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3beta has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3beta was involved in amyloid-beta (Abeta)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Abeta activates GSK-3beta through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Abeta-activated GSK-3beta induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3beta can induce memory deficits in vivo; and that inhibition of GSK-3alpha (an isoform of GSK-3beta) reduces Abeta production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease.

Publication types

  • Review

MeSH terms

  • Aging / physiology
  • Alzheimer Disease / complications
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / pathology*
  • Brain / enzymology*
  • Brain / pathology*
  • Cognition Disorders / complications
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Neurofibrillary Tangles / pathology
  • Phosphorylation
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • Glycogen Synthase Kinase 3