title: 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.
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 that mTOR is 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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life Sciences, Tel Aviv University Tel Aviv 69978, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Avrahami
authors.forename: Dorit
authors.initials: D
authors.lastname: Farfara
authors.forename: Maya
authors.initials: M
authors.lastname: Shaham-Kol
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
mesh_terms: D000143:Acids / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000143:Acids; D016229:Amyloid beta-Peptides; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3