1,720,973 research outputs found
Investigating how ageing contributes to tauopathy: implications for Alzheimer’s Disease
No full textAge is the single biggest risk factor for Alzheimer’s Disease (AD). It is currently unclear how cellular changes that occur during ageing predispose people to the formation of the tau and Aβ pathologies found in AD. Recently, the same cellular pathways that are implicated in ageing have also been found to be altered in AD. These pathways include those involved in the maintenance of protein turnover such as mTORC1 signalling and autophagy. To understand how ageing contributes to the risk of developing AD we sought to analyse how these pathways change with age and how they can impact on the tau pathology found in AD. To initially understand age-related changes in tau, different tau isoforms of human tau were expressed in Drosophila to assess age-related changes in tau-mediated phenotypes and pathologies. Htau0N3R expression caused reduced lifespan and deficits in age-related climbing ability compared with controls. Htau0N4R induced less severe effects on both longevity and climbing than htau0N3R flies. Specific phosphorylation sites were also found to be altered, with age, in htau0N3R but not in htau0N4R flies, implicating phosphorylation in age-related phenotypes. Both isoforms of htau were found to accumulate with age, suggesting dysfunction in pathways that regulate protein turnover. In addition, htau0N3R flies were assessed for changes in circadian rhythms. Expression of htau0N3R in the central clock neurons induced slowing of the circadian clock. htau0N3R was also demonstrated to induce deficits in short term memory tested using a new high throughput adaptation of a learning and memory assay. To understand how pathways involved in regulation of protein turnover are altered in normal ageing, components of both mTORC1 signalling and autophagy pathways were assessed biochemically for age-related changes in human cortical brain tissue resected from differently aged patients undergoing neurosurgery. The mTORC1 signalling pathway was found to be less active with age and this was correlated with increased levels of autophagy and reduced total and phospho tau levels. Genetic up-regulation of autophagy in htau0N3R Drosophila similarly resulted in reduced deficits in locomotion and memory, together with reduced age-related accumulation of total and phospho htau0N3R protein. These studies demonstrate the importance of pathways that regulate protein turnover, such as mTORC1 signalling and autophagy, in both ageing and disease. Understanding how these pathways become dysregulated in disease has the potential to lead to new therapeutic targets for AD
Microtubule stabilising peptides rescue tau phenotypes in-vivo
No full textThe microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease
Suppression of tau‐induced phenotypes by vitamin E demonstrates the dissociation of oxidative stress and phosphorylation in mechanisms of tau toxicity
No full textVarious lines of evidence implicate oxidative stress in the pathogenic mechanism(s) underpinning tauopathies. Consequently, antioxidant therapies have been considered in clinical practice for the treatment of tauopathies such as Alzheimer's disease (AD), but with mixed results. We and others have previously reported increased protein oxidation upon expression of both human 0N3R (hTau
0N3R) and 0N4R (hTau
0N4R) tau in vivo. Building on these studies, we demonstrate here the suppression of hTau
0N3R associated phenotypes in Drosophila melanogaster after treatment with vitamin C or vitamin E. Curiously the rescue of phenotype was seen without alteration in total tau level or alteration in phosphorylation at a number of disease-associated sites. Moreover, treatment with paraquat, a pro-oxidant drug, did not exacerbate the hTau
0N3R phenotypes. This result following paraquat treatment is reminiscent of our previous findings with hTau
0N4R which also causes greater oxidative stress when compared to hTau
0N3R but has a milder phenotype. Collectively our data imply that the role of oxidative stress in tau-mediated toxicity is not straight forward and there may be isoform-specific effects as well as contribution of other factors. This may explain the ambiguous effects of anti-oxidant treatments on clinical outcome in dementia patients. (Figure presented.).
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Tau-mediated axonal degeneration is prevented by activation of the Wld<sup>S</sup> pathway
No full textTauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau. The neuronal changes evident in Tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by expression of WldS. In a Drosophila model of tauopathy in which expression of human Tau protein (hTau0N3R) leads to progressive age-dependent phenotypes, activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after hTau-mediated degeneration had become established. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in hTau0N3R –expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by hTau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies
Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers
No full textAggregation of highly phosphorylated tau is a hallmark of Alzheimer’s disease and other tauopathies. Nevertheless, animal models demonstrate that tau-mediated dysfunction/toxicity may not require large tau aggregates but instead may be caused by soluble hyper-phosphorylated tau or by small tau oligomers. Challenging this widely held view, we use multiple techniques to show that insoluble tau oligomers form in conditions where tau-mediated dysfunction is rescued in vivo. This shows that tau oligomers are not necessarily always toxic. Furthermore, their formation correlates with increased tau levels, caused intriguingly, by either pharmacological or genetic inhibition of tau kinase glycogen-synthase-kinase-3beta (GSK-3?). Moreover, contrary to common belief, these tau oligomers were neither highly phosphorylated, and nor did they contain beta-pleated sheet structure. This may explain their lack of toxicity. Our study makes the novel observation that tau also forms non-toxic insoluble oligomers in vivo in addition to toxic oligomers, which have been reported by others. Whether these are inert or actively protective remains to be established. Nevertheless, this has wide implications for emerging therapeutic strategies such as those that target dissolution of tau oligomers as they may be ineffective or even counterproductive unless they act on the relevant toxic oligomeric tau species
Low endogenous and chemical induced heat shock protein induction in a 0N3Rtau-expressing drosophila larval model of Alzheimer’s disease
No full textReduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease. Although pan-neuronal tau expression augmented the induction of hsp70 following heat shock, several candidate HSP inducing compounds induced hsp70 protein in mammalian cells in vitro but did not detectably induce hsp70 mRNA or protein in tau expressing larvae. The hsp90 inhibitors 17-AAG and radicicol nevertheless caused a dose-dependent reduction in total human tau levels in transgenic larvae without specifically altering tau hyperphosphorylated at S396/S404. These and several other HSP modulating compounds also failed to rescue the tau-induced larval locomotion deficit in this model. Tau pathology in tau-expressing larvae, therefore, induces weak de novo HSP expression relative to other neurodegenerative disease models, and unlike these disease models, pharmacological manipulation of the hsp90 pathway does not lead to further induction of the heat shock response. Forthcoming studies investigating the effects of HSP induction on tau-mediated dysfunction/toxicity in such models will require more robust, non-pharmacological (perhaps genetic) means of manipulating the hsp90 pathway
Using Drosophila models of neurodegenerative diseases for drug discovery
No full textIntroduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies.Areas covered: This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways.Expert opinion: Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions. <br/
Modelling tauopathies in Drosophila: insights from the fruit fly.
Get PDFDrosophila melanogaster is an experimentally tractable model organism that has been used successfully to model aspects of many human neurodegenerative diseases. Drosophila models of tauopathy have provided valuable insights into tau-mediated mechanisms of neuronal dysfunction and death. Here we review the findings from Drosophila models of tauopathy reported over the past ten years and discuss how they have furthered our understanding of the pathogenesis of tauopathies. We also discuss the multitude of technical advantages that Drosophila offers, which make it highly attractive as a model for such studies
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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