Inhibition of glycogen synthase kinase-3 ameliorates β-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the alzheimer disease mouse model: In vivo and in vitro studies

Limor Avrahami, Dorit Farfara, Maya Shaham-Kol, Robert Vassar, Dan Frenkel*, Hagit Eldar-Finkelman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

Accumulation of β-amyloid (Aβ) deposits is a primary pathological feature of Alzheimer disease that is correlated with neurotoxicity and cognitive decline. The role of glycogen synthase kinase-3 (GSK-3) in Alzheimer disease pathogenesis has been debated. To study the role of GSK-3 in Aβ pathology, we used 5XFAD mice co-expressing mutated amyloid precursor protein and presenilin-1 that develop massive cerebral Aβ loads. Both GSK-3 isozymes (α/β) were hyperactive in this model. Nasal treatment of 5XFAD mice with a novel substrate competitive GSK-3 inhibitor, L803-mts, reduced Aβ deposits and ameliorated cognitive deficits. Analyses of 5XFAD hemi-brain samples indicated that L803-mts restored the activity of mammalian target of rapamycin (mTOR) and inhibited autophagy. Lysosomal acidification was impaired in the 5XFAD brains as indicated by reduced cathepsin D activity and decreased N-glycoyslation of the vacuolar ATPase subunit V0a1, a modification required for lysosomal acidification. Treatment with L803-mts restored lysosomal acidification in 5XFAD brains. Studies in SH-SY5Y cells confirmed that GSK-3α and GSK-3β impair lysosomal acidification and that treatment with L803-mts enhanced the acidic lysosomal pool as demonstrated in LysoTracker Red-stained cells. Furthermore, L803-mts restored impaired lysosomal acidification caused by dysfunctional presenilin-1. We provide evidence thatmTORis a target activated by GSK-3 but inhibited by impaired lysosomal acidification and elevation in amyloid precursor protein/Aβ loads. Taken together, our data indicate that GSK-3 is a player in Aβ pathology. Inhibition of GSK-3 restores lysosomal acidification that in turn enables clearance of Aβ burdens and reactivation of mTOR. These changes facilitate amelioration in cognitive function.

Original languageEnglish (US)
Pages (from-to)1295-1306
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number2
DOIs
StatePublished - Jan 11 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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