GSK-3α/β kinases and amyloid production in vivo

Abstract

Arising from C. J. Phiel, C. A. Wilson, V. M.-Y. Lee & P. S. Klein 423, 435-439 (2003)A major unresolved issue in Alzheimer's disease is identifying the mechanisms that regulate proteolytic processing of amyloid precursor protein (APP)-glycogen synthase kinase-3 (GSK-3) isozymes are thought to be important in this regulation. Phiel et al. proposed that GSK-3α, but not GSK-3β, controls production of amyloid. We analysed the proteolytic processing of mouse and human APP in mouse brain in vivo in five different genetic and viral models. Our data do not yield evidence for either GSK-3α-mediated or GSK-3β-mediated control of APP processing in brain in vivo.

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

“…Moreover, GSK3β is the predominant isoform in the brain and therefore has been implicated in many CNS disorders (74). However, Jaworski et al recently showed the GSK3α/β knockout mice did not show any changes to APP processing and Aβ production (52). This could be due to a physiological compensation of BACE1 expression in the KO mice compared with the acute effect of the GSK3 inhibitor.…”

“…GSK3β has been found to phosphorylate the tau protein on various conserved sites and contribute to tau hyperphosphorylation and neurofibrillary tangle formation (49,50). GSK3α was reported to regulate Aβ production by positively modulating the γ-secretase complex (51), although this finding has recently been challenged (52). Inhibition of GSK3 activity with the commonly known GSK3 inhibitors LiCl and valproic acid in cell culture (53) and animal models of AD decreased Aβ production (51,54).…”

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

“…Initially, it was shown that GSK-3␣ enhanced ␥-secretase-mediated A␤ peptide production in CHO cells overexpressing APP (14). A recent report challenged these results and showed that knock-out of GSK-3␣ or GSK-3␤ in the mouse brain did not alter levels of APP metabolites or A␤ peptides (15). Other studies showed that treatment with GSK-3 inhibitors, lithium, or NP12 or silencing of GSK-3␣ with hairpin RNA constructs reduced A␤ deposition in various AD mouse models (14,16,17), yet our understanding of mechanisms behind GSK-3 regulation of A␤ pathology is limited.…”

Structural and Functional Characterization of Nrf2 Degradation by the Glycogen Synthase Kinase 3/β-TrCP Axis

“…Transgenic mice with the GSK-3␤ gene flanked by loxP sites were crossed with mice expressing Cre recombinase under the Thy1 gene promoter. Mice with two floxed GSK-3␤ alleles but not expressing Cre recombinase (ϪCre mice) were used as controls for the double-transgenic mice that express Cre recombinase (ϩCre mice) and that lack both GSK-3␤ alleles postnatally and only in neurons (18). All experiments were approved by the KU Leuven ethical commission, according to institutional Belgian and European guidelines (European Council Directives 86/609/EEC and 2003/65/EC).…”

“…Mice with postnatal neuronal deficiency of GSK-3␤ were generated by the Cre/lox system as described previously (18). Transgenic mice with the GSK-3␤ gene flanked by loxP sites were crossed with mice expressing Cre recombinase under the Thy1 gene promoter.…”