Tau hyperphosphorylation affects Smad 2/3 translocation.
Transforming growth factors beta (TGFbeta) regulate multiple biological activities. TGFbeta activation of the Smad pathway results in activation of genes encoding extracellular matrix molecules, proteases, protease activators and protease inhibitors. In Alzheimer's disease (AD), TGFbeta protein and mRNA levels are raised, which would be expected to be neuroprotective. However, recent observations suggest that TGFbeta-Smad signalling is disrupted by the hyperphosphorylation of tau, the primary component of neurofibrillary tangles: phosphorylated Smad2/3 (pSmad 2/3) co-localises with phosphorylated tau in the neuronal cytoplasm and levels are reduced in the nucleus. We have investigated whether in vitro induction of tau hyperphosphorylation influences pSmad 2/3 localisation in rat primary cortical cells. Treatment with okadaic acid, a protein phosphatase 1 and 2A inhibitor caused hyperphosphorylation of tau at epitopes hyperphosphorylated in AD and disrupted pSmad 2/3 translocation into the nucleus. The disruptive effect of tau phosphorylation on pSmad 2/3 translocation was confirmed by treatment of primary cortical cells with synthetic oligomeric A beta(1-42), a more physiologically relevant model of AD. Our findings suggest that despite the increased level of TGFbeta in AD, the TGFbeta-Smad signalling pathway is impeded within neurones due to sequestration of pSmad 2/3 by hyperphosphorylated tau. This may compromise neuroprotective actions of TGFbeta and contribute to neurodegeneration in AD.
Baig
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Dementia Research Group, Institute of Clinical Neurosciences, Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, UK. shabnam.baig@bristol.ac.uk
van Helmond
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Z
Love
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D021581:Active Transport, Cell Nucleus; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D019319:Okadaic Acid / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C489131:Mapt protein, rat; D010446:Peptide Fragments; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019319:Okadaic Acid