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Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers

Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers
Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers
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-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.
Cowan, Catherine
b4f6d80b-ceb3-4dd2-8507-0414855d9992
Quraishe, Shmma
cfc3aed4-f120-41aa-9127-0fc26c657ad2
Hands, Sarah
a558692f-fad3-4d9c-ada1-abd95946512c
Sealey, Megan
f4f4e7b5-b160-434c-b5e7-a6468283bfdd
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Allan, Douglas W.
24b811e0-7122-48e2-bcc0-15518612cefe
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Cowan, Catherine
b4f6d80b-ceb3-4dd2-8507-0414855d9992
Quraishe, Shmma
cfc3aed4-f120-41aa-9127-0fc26c657ad2
Hands, Sarah
a558692f-fad3-4d9c-ada1-abd95946512c
Sealey, Megan
f4f4e7b5-b160-434c-b5e7-a6468283bfdd
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Allan, Douglas W.
24b811e0-7122-48e2-bcc0-15518612cefe
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119

Cowan, Catherine, Quraishe, Shmma, Hands, Sarah, Sealey, Megan, Mahajan, Sumeet, Allan, Douglas W. and Mudher, Amritpal (2015) Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers. Scientific Reports, 5, [17191]. (doi:10.1038/srep17191). (PMID:26608845)

Record type: Article

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-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.

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More information

Accepted/In Press date: 12 October 2015
e-pub ahead of print date: 26 November 2015
Published date: 26 November 2015
Organisations: Institute for Life Sciences, Chemical Biology Group

Identifiers

Local EPrints ID: 384824
URI: http://eprints.soton.ac.uk/id/eprint/384824
PURE UUID: c20b0f63-7861-4c15-8e29-44fab9f1a39c
ORCID for Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666

Catalogue record

Date deposited: 13 Jan 2016 12:32
Last modified: 10 Nov 2021 03:18

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Contributors

Author: Catherine Cowan
Author: Shmma Quraishe
Author: Sarah Hands
Author: Megan Sealey
Author: Sumeet Mahajan ORCID iD
Author: Douglas W. Allan
Author: Amritpal Mudher

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