Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3

Abstract

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist after cessation of the initial trigger. Regarding AD, GSK-3 has been shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in PHF (paired helical filament)-tau and GSK-3 activity contributes both to ␤-amyloid production and to ␤-amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3␤ mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here, we exploit the conditional system used to generate Tet/GSK-3␤ mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert after restoration of normal GSK-3 levels. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics.

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

“…L'augmentation de l'activité de la GSK-3 dans les cerveaux de patients atteints de MA coïncide au niveau spatiotemporel avec les DNF [2]. La GSK-3 surexprimée dans le cerveau de souris transgéniques provoque l'hyperphosphorylation de la protéine Tau, le désassemblage des microtubules et l'apparition de DNF [3,4]. > Le vieillissement de la population entraîne une augmentation spectaculaire de l'incidence des maladies neurodégénératives dans les pays industrialisés.…”

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

“…In addition, PI3K/Akt signaling regulates translation by activating mTOR (mammalian target of rapamycin) (Ruggero and Sonenberg, 2005), and suppresses the activity of glycogen synthase kinase-3 (GSK-3) (Cross et al, 1995) that has been implicated in neuronal cell death, tau overphosphorylation and production of A␤ peptides (for review, see Kaytor and Orr, 2002;Bhat et al, 2004). The importance of GSK-3␤ in brain function is underlined by previous data showing increased neurodegeneration, Alzheimer's disease (AD)-like tau hyperphosphorylation, and behavioral abnormalities in GSK-3␤ conditional knock-out mice, all of which were reversed after restoration of normal GSK-3␤ levels (Engel et al, 2006). PI3K/Akt signaling is of central importance for neuronal physiology.…”

Progressive supranuclear palsy: new concepts

“…Glycogen synthase kinase 3 (GSK-3) may play a role in tau diseases because it can phosphorylate tau in vivo, and inhibition of this enzyme in transgenic mice and in drosophila leads to functional improvement 48,49 . Lithium seems to be a GSK-3 inhibitor in mice with increased activity of this enzyme, preventing neuropathologic changes 50 .…”