GSK-3 and lysosomes meet in Alzheimer's disease

Limor Avrahami, Hagit Eldar-Finkelman

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant regulation of glycogen synthase kinase-3 (GSK-3) is implicated in Alzheimer's disease (AD), but the mechanisms involved remain elusive. Our recent study shows that GSK-3 impairs lysosomal acidification and that inhibition of GSK-3 re-acidified lysosomes in brains of AD mice. This effect was accompanied by reductions in ß-amyloid pathology and amelioration of cognitive deficits. Presenilin-1 (PS1) is an essential factor in lysosomal acidification. To determine whether the inhibition of GSK-3 restores lysosomal malfunction caused by dysfunctional PS1, we treated MEF cells deficient in presenilin proteins (MEF-PS1/2-/-) with a selective substrate competitive GSK-3 inhibitor, L803-mts. L803-mts enhanced the acidic lysosomal pool in MEF-PS1/2-/- cells and increased levels of activated cathepsin D in the lysosomes. We conclude that GSK-3 and PS1 operate via similar mechanisms to disrupt lysosomal acidification. Importantly, these data indicate that GSK-3 inhibitors have potential in treatment of conditions associated with defective PS1.

Original languageEnglish
Article numbere25179
JournalCommunicative and Integrative Biology
Volume6
Issue number5
DOIs
StatePublished - 2013

Keywords

  • Alzheimer's disease
  • Aβ pathology
  • GSK-3
  • Lysosome
  • Presenilin-1

All Science Journal Classification (ASJC) codes

  • General Agricultural and Biological Sciences

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