title: Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers.
abstract: Aggregation 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-3β). 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.
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cowan
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Shmma
authors.initials: S
authors.lastname: Quraishe
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hands
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Sealey
authors.affiliation: Institute of Life Sciences and Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Sumeet
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: Department of Cellular and Physiological Sciences, Life Science Institute, University of British Columbia, Vancouver, V6T 1Z3, Canada.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Allan
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Amritpal
authors.initials: A
authors.lastname: Mudher
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster / Q000378:metabolism / Q000648:ultrastructure; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D012995:Solubility; D013059:Spectrum Analysis, Raman; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3