GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila

Abstract

The tauopathies are a group of disorders characterised by aggregation of the microtubuleassociated protein tau and include Alzheimer's disease (AD) and the fronto-temporal dementias (FTD). We have used Drosophila to analyse how tau abnormalities cause neurodegeneration. By selectively co-expressing wild-type human tau (0N3R isoform) and a GFP vesicle marker in motorneurons, we examined the consequences of tau overexpression on axonal transport in vivo. The results show that overexpression of tau disrupts axonal transport causing vesicle aggregation and this is associated with loss of locomotor function. All these effects occur without neuron death. Co-expression of constitutively active glycogensynthase kinase-3b (GSK-3b) enhances and two GSK-3b inhibitors, lithium and AR-A014418, reverse both the axon transport and locomotor phenotypes, suggesting that the pathological effects of tau are phosphorylation dependent. These data show that tau abnormalities significantly disrupt neuronal function, in a phosphorylation-dependent manner, before the classical pathological hallmarks are evident and also suggest that the inhibition of GSK-3b might have potential therapeutic benefits in tauopathies. Keywords: Alzheimer's disease; axonal transport; Drosophila; GSK-3b; lithium; tau Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease (AD) and the fronto-temporal dementias (FTD), characterised by aggregation of the microtubule-associated protein, tau, into neurofibrillary tangles (NFTs). The finding that mutations in the tau gene give rise to familial FTD 1 proved that abnormalities in tau are sufficient to cause neurodegeneration. However, the cellular mechanisms by which tau abnormalities disrupt neuronal function and lead to neurodegeneration have not been elucidated. Furthermore, in the tauopathies at least three tau protein abnormalities are observed: hyperphosphorylation, altered expression and filament formation; and it is not clear which of these plays a primary role in the disease process and which is a secondary consequence.We have previously demonstrated that overexpression of tau causes neurodegeneration in Drosophila without forming filamentous aggregates.2 Others have subsequently confirmed and extended these findings by illustrating that overexpression of FTDP-17 mutant tau also induces neurodegeneration in Drosophila without the formation of neurofibrillary aggregates. 3More recently it has been shown that hyperphosphorylation of overexpressed tau not only exacerbates the neurodegeneration seen with tau alone but also stimulates filament formation leading to NFT formation in Drosophila.4 These findings collectively demonstrate that although hyperphosphorylation, and possibly filament formation, can exacerbate taumediated neurodegeneration, overexpression of wildtype (wt) tau alone is sufficient to cause neurodegeneration. The molecular events underlying this have not been elucidated.There are many ways by which tau overexpression could disrupt neuronal homeostasis and cause neu...

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…High levels of tau phosphorylation disrupt neuronal vesicle transport by compromising microtubule stability (Mudher et al 2004), and consequently lead to variable degrees of neuronal dysfunction and premature death of signaling defective mutant mice (Sheldon et al 1997;Trommsdorff et al 1999;Brich et al 2003). Intriguingly, genetic deficiency of tau prevents APP/Ab-induced cognitive defects as well as excitotoxicity in mice , indicating that the presence of abnormally phosphorylated tau, rather than its functional loss, is the likely reason for the severe motor defects that cause the premature death in the Reelin pathway mutants.…”

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

“…In cultured neurons, lithium has been shown to suppress tau phosphorylation, enhance tau-microtubule binding, and promote microtubule assembly (20)(21)(22). In vivo, lithium has been shown to reduce insoluble tau (23) and ameliorate axonal transport deficiencies in transgenic Drosophila (24). Phiel et al (25) have recently shown that lithium chloride (LiCl) significantly decreases ␤-amyloid (A␤) production in vivo through inhibition of GSK-3 activity.…”

Pharmacogenetic Analysis of Lithium-induced Delayed Aging in Caenorhabditis elegans

“…The C. elegans ortholog of this neuroprotective protein (CED-9) (15) functions to prevent cell death during development (16,17). In models of neurological disease, Li ϩ has been shown to reverse axon transport deficiencies in transgenic Drosophila (18) and reduce insoluble tau (19), abrogate axonal degeneration (20), and decrease ␤-amyloid production in mice (21). In studies on cultured cerebellar granule cells of rats, Li ϩ protected against apoptosis induced by anticonvulsants (22).…”