Filamin-A and Myosin VI colocalize with fibrillary Tau protein in Alzheimer's disease and FTDP-17 brains

Feuillette, Sébastien; Deramecourt, Vincent; Laquerrière, Annie; Duyckaerts, Charles; Delisle, Marie–Bernadette; Maurage, Claude‐Alain; Blum, David; Buée, Luc; Frébourg, Thierry; Campion, Dominique; Lecourtois, Magalie

doi:10.1016/j.brainres.2010.05.007

Cited by 27 publications

(23 citation statements)

References 24 publications

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“…This interaction was identified and characterized for the first time in similar purified protein assay involving tau MTbinding domains and the portion of the proline-rich domain that interacts directly with F-actin (He et al, 2009). Similarly, this interaction has been identified in PC12 cells (Yu and Rasenick, 2006) and in a Drosophila model of AD (Fulga et al, 2006). The consequences of the interaction between tau and F-actin are a stabilization of actin filaments and their organization into bundles.…”

Section: Discussionmentioning

confidence: 64%

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Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

et al. 2014

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Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates in synaptic function as part of the molecular pathway leading to amyloid-beta (A␤)-driven synaptotoxicity in the context of Alzheimer's disease. Here, we report the implication of tau in the profound functional synaptic modification associated with synaptic plasticity. By exposing murine cultured cortical neurons to a pharmacological synaptic activation, we induced translocation of endogenous tau from the dendritic to the postsynaptic compartment. We observed similar tau translocation to the postsynaptic fraction in acute hippocampal slices subjected to long-term potentiation. When we performed live confocal microscopy on cortical neurons transfected with human-tau-GFP, we visualized an activity-dependent accumulation of tau in the postsynaptic density. Coprecipitation using phalloidin revealed that tau interacts with the most predominant cytoskeletal component present, filamentous actin. Finally, when we exposed cortical cultures to 100 nM human synthetic A␤ oligomers (A␤o's) for 15 min, we induced mislocalization of tau into the spines under resting conditions and abrogated subsequent activity-dependent synaptic tau translocation. These changes in synaptic tau dynamics may rely on a difference between physiological and pathological phosphorylation of tau. Together, these results suggest that intense synaptic activity drives tau to the postsynaptic density of excitatory synapses and that A␤o-driven tau translocation to the spine deserves further investigation as a key event toward synaptotoxicity in neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 64%

“…Among several synaptically located proteins, actin is of particular interest for its potential capacity to interact with human tau (Fulga et al, 2006;Yu and Rasenick, 2006;He et al, 2009). We investigated whether tau interacts with actin, the most predominant cytoskeleton element of the synapse.…”

Section: Tau Interacts With Filamentous Actin In the Synapsementioning

confidence: 99%

Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

et al. 2014

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“…While the unfolded protein response protects against tau neurotoxicity [49], lysosomal dysfunction [50], [51], abnormal bundling and accumulation of F-actin [52] and other cytoskeletal proteins [53], [54], oxidative stress [55], and tau phosphorylation [56], [57], [58], [59] are among the pathways shown to promote tau neurotoxicity in vivo . With respect to the rough eye phenotype in tau 17kD -expressing flies, we are not certain of the mechanism controlling the tau-induced neurotoxicity we observe.…”

Section: Discussionmentioning

confidence: 99%

Implicating Calpain in Tau-Mediated Toxicity In Vivo

et al. 2011

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Alzheimer's disease and other related neurodegenerative disorders known as tauopathies are characterized by the accumulation of abnormally phosphorylated and aggregated forms of the microtubule-associated protein tau. Several laboratories have identified a 17 kD proteolytic fragment of tau in degenerating neurons and in numerous cell culture models that is generated by calpain cleavage and speculated to contribute to tau toxicity. In the current study, we employed a Drosophila tauopathy model to investigate the importance of calpain-mediated tau proteolysis in contributing to tau neurotoxicity in an animal model of human neurodegenerative disease. We found that mutations that disrupted endogenous calpainA or calpainB activity in transgenic flies suppressed tau toxicity. Expression of a calpain-resistant form of tau in Drosophila revealed that mutating the putative calpain cleavage sites that produce the 17 kD fragment was sufficient to abrogate tau toxicity in vivo. Furthermore, we found significant toxicity in the fly retina associated with expression of only the 17 kD tau fragment. Collectively, our data implicate calpain-mediated proteolysis of tau as an important pathway mediating tau neurotoxicity in vivo.

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“…cheerio had been identified also in a previous similar screen [41]. Filamin-A and MyosinVI were further found to colocalize with fibrillary hTau protein in AD and FTD brains [65]. The Feany lab showed that actin might be a critical mediator of Tau-induced neurotoxicity [66].…”

Section: Pathogenic Mechanisms Of Tauopathiesmentioning

confidence: 99%

DrosophilaModels of Tauopathies: What Have We Learned?

Gistelinck

Lambert

Callaerts

et al. 2012

International Journal of Alzheimer's Disease

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Aggregates of the microtubule-associated protein Tau are neuropathological hallmark lesions in Alzheimer's disease (AD) and related primary tauopathies. In addition, Tau is genetically implicated in a number of human neurodegenerative disorders including frontotemporal dementia (FTD) and Parkinson's disease (PD). The exact mechanism by which Tau exerts its neurotoxicity is incompletely understood. Here, we give an overview of how studies using the genetic model organism Drosophila over the past decade have contributed to the molecular understanding of Tau neurotoxicity. We compare the different available readouts for Tau neurotoxicity in flies and review the molecular pathways in which Tau has been implicated. Finally, we emphasize that the integration of genome-wide approaches in human or mice with high-throughput genetic validation in Drosophila is a fruitful approach.

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Filamin-A and Myosin VI colocalize with fibrillary Tau protein in Alzheimer's disease and FTDP-17 brains

Cited by 27 publications

References 24 publications

Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

Implicating Calpain in Tau-Mediated Toxicity In Vivo

DrosophilaModels of Tauopathies: What Have We Learned?

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