Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease
Abstract
Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (Abeta(42)). It is generally believed that the hyper-phosphorylated tau and oligomeric Abeta(42) are responsible for the neuronal dysfunction and cognitive impairments that underlie the early stages of AD, but the mechanism by which they interact in the pathogenic process is not clear. Mounting evidence suggests that Abeta(42) pathology lies upstream of hyper-phosphorylated tau pathology. Similarly much is being learnt about how each protein affects neuronal function. However, the impact that either pathological protein has on neuronal dysfunction caused by the other is not extensively studied. We have investigated this in a Drosophila model of AD in which we express both phosphorylated human tau (tau(wt)) and oligomeric Abeta(42). We find that expression of tau(wt) causes neuronal dysfunction by disrupting axonal transport and synaptic structure, and that this leads to behavioural impairments and reduced lifespan. Co-expression of Abeta(42) with tau(wt) increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tau(wt)/Abeta(42) and flies with LiCl ameliorates the exacerbating effect of Abeta(42), suggesting that GSK-3beta may be involved in the mechanism by which Abeta(42) and tau(wt) interact to cause neuronal dysfunction. Conversely to the effect of Abeta(42), mimicking the…
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Inhibition or genetic reduction of GSK-3β ameliorates tau-related deficits.
“many investigators have shown that either inhibition or genetic reduction of GSK-3β ameliorates tau-related deficits (94–99).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [99]
Suppression of Aβ42 toxicity supports previous reports in cell, mouse and fly models in which Aβ42 induces GSK-3β activity and inhibition or reduction of GSK-3β ameliorates Aβ42-induced degeneration.
“Suppression of Aβ42 toxicity supports previous reports in cell, mouse and fly models in which Aβ42 induces GSK-3β activity and inhibition or reduction of GSK-3β ameliorates Aβ42-induced degeneration, either independent of or in concert with tau toxicity (99–101).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [99]
Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases.
“Drosophila models expressing human tau recapitulate key features of human tauopathies, including progressive neurodegeneration and phosphorylation at AD-related sites via conserved kinases [41, 44, 53, 59–63].”
Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD.
“Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”
In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK.
“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
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References 61 · Cited by 83
- Authors
- Folwell, J., Cowan, C. M., Ubhi, K. K., Shiabh, H., Newman, T. A., Shepherd, D., & Mudher, A.
- Affiliations
- University of Southampton (GB)
- Corresponding author
- Mudher, Amritpal
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 223
- Issue
- 2
- Pages
- 401-409
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2043624650
- Cited by
- 83
- References
- 61
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 5 · 2014: 9 · 2013: 9 · 2012: 4
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Alzheimer's Society
- Wessex Medical Research
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, tau hyperphosphorylation, Drosophila model, axonal transport, synaptic structure, behavioural impairment, lifespan, lithium chloride, GSK3β, Wnt signaling, Dishevelled, tau phosphorylation, neurofibrillary tangles, neuritic plaques
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Axonal Transport, Disease Models, Animal, Drosophila, Humans, Locomotion, Longevity, Neuromuscular Junction, Neurons, Peptide Fragments, Phenotype, Phosphorylation, Synapses, Signal Transduction, Down-Regulation, Amyloid beta-Peptides, tau Proteins, Drosophila Proteins, Animals, Genetically Modified, Glycogen Synthase Kinase 3, Wnt1 Protein
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