S4-03-06: Exploring reversal of Alzheimer’s disease like phenotype in a mouse model with conditional overexpression of GSK-3

Abstract

Glycogen synthase kinase–3 (GSK3) 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 upon cessation of the initial trigger. Regarding AD, GSK–3 has been shown to be upregulated in patients' brain. Furthermore, GSK–3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filament (PHF)–tau and GSK–3 activity contributes both to β–amyloid production and to β–amyloid–mediated neuronal death. In good agreement, mice with conditional overexpression of GSK–3 in forebrain neurons (Tet/GSK–3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here we aim to exploit the conditional system used to generate Tet/GSK–3β mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK–3 activity are susceptible to revert upon restoration of normal GSK–3 levels.