Roles of Glycogen Synthase Kinase-3 in Alzheimer's Disease: From Pathology to Treatment Target

Hsing Cheng Liu, Sy Jye Leu, De Maw Chuang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unknown cause, and as of yet there is no effective treatment. The neuropathological hallmarks of AD include amyloid plaques and neurofibrillary tangle (NFT) deposits. There is evidentiary support for amyloid deposition being the primary influence driving AD pathogenesis, commonly referred to as the amyloid hypothesis of AD. But brain amyloid load is not correlated with AD severity; instead, NFT formation has been shown to be associated with disease progression. Therefore, advocates of the tau hypothesis strongly postulate that NFT accumulation is critical for neuronal loss and AD development. Hence, inhibition of NFT formation/accumulation is one of the treatment strategies to combat AD. NFTs consist of aggregations of paired helical hyperphosphorylated tau protein, one of the major microtubule-associated proteins. The hyperphosphorylation of tau impairs its normal maintenance function for cytoskeleton stability, and induces a toxic sequestration of normal tau and other microtubule-associated proteins. Glycogen synthase kinase-3 (GSK-3) is the main enzyme that phosphorylates tau, and an increase in GSK-3 activity has been observed in AD patients. GSK-3 inhibition by lithium, a major mood stabilizer that is used to treat bipolar disorder, has been shown to reduce tau phosphorylation and even decrease amyloid burden in the brain of AD animal models. This supports the notion of GSK-3 inhibition as a potential avenue for AD treatment.

Original languageEnglish
Pages (from-to)135-139
Number of pages5
JournalJournal of Experimental and Clinical Medicine(Taiwan)
Volume4
Issue number3
DOIs
Publication statusPublished - Jun 2012

Keywords

  • Alzheimer's disease
  • Beta-amyloid
  • Glycogen synthase kinase-3
  • Lithium
  • Neurofibrillary tangle
  • Tau

ASJC Scopus subject areas

  • Medicine(all)

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