Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

Abstract

Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…Although this effect of lithium in vitro was mimicked by transfection with siRNA of GSK-3a but not GSK-3b , other in vitro and in vivo studies found that GSK-3b inhibition also mimicked the ability of lithium or VPA to suppress the process of Ab formation from APP (Su et al, 2002(Su et al, , 2004Qing et al, 2008). A recent study in an adultonset Drosophila model of AD demonstrated a novel mechanism, whereby GSK-3 directly regulated Ab42 levels in the absence of any effects on APP processing (Sofola et al, 2010).…”

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

“…28,29,30 In A -overexpressing transgenic models for AD, lithium treatment consistently decreases A levels, GSK-3 activity and tau phosphorylation. 29,31,32,33,34 In such models, lithium is reported to prevent A toxicity, 32 preserve dendritic structure, 31 promote neurogenesis 34 and rescue A -induced cognitive impairment. 31,33,34 Similarly, in transgenic mice that overexpress pathogenic mutant tau, lithium treatment reduced levels of hyperphosphorylation.…”

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

“…In recent years, Drosophila models for Alzheimer's disease were developed (Finelli et al, 2004;Greeve et al, 2004;Crowther et al, 2005), and several factors (such as insulindegrading enzyme, apolipoprotein E, oxidative stress) known to be related to Alzheimer's disease were studied with these Drosophila models (Rival et al, 2009;Sarantseva et al, 2009;Sofola et al, 2010;Tsuda et al, 2010;Ling and Salvaterra, 2011). Work from these groups has shown that Drosophila recapitulates several pathological features also seen in Alzheimer's disease.…”