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Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model

Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model
Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model

Adeno-associated virus serotype 6 (AAV6) viral vectors encoding mutant and normal tau were used to produce focal tau pathology. Two mutant forms of tau were used; the P301S tau mutation is associated with neurofibrillary tangle formation in humans, and the 3PO mutation leads to rapid tau aggregation and is associated with pathogenic phosphorylation and cytotoxicity in vitro. We show that adeno-associated viral injection into entorhinal cortex of normal and tau knockout animals leads to local overexpression of tau, and the presence of human tau in axons projecting to and emanating from the entorhinal cortex. Starting at 2 months and increasing by 6 months post-injection neurons expressing mutant tau developed hyperphosphorylated tau pathology, in addition to dystrophic neurites. There was neuronal loss in tau-expressing regions, which was similar in normal and in TASTPM mice injected with mutant tau. There was neuroinflammation around plaques, and in regions expressing mutant tau. We saw no evidence that mutant tau had affected amyloid-beta pathology or vice versa. Morris water maze behavioral tests demonstrated mild memory impairment attributable to amyloid-beta pathology at 2 and 4 months, with severe impairment at 6 months in animals receiving adeno-associated viral-3PO. Therefore, TASTPM mice injected with mutant tau displayed many of the main features characteristic of human Alzheimer's disease patients and might be used as a model to test new drugs to ameliorate clinical features of Alzheimer's disease.

Alzheimer's Disease, Adeno-associated virus, Alzheimer's precursor protein, tau, tauopathy, viral vectors, memory, neurodegeneraation
1355-68
Dassie, Elisa
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Andrews, Melissa R.
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Bensadoun, Jean-Charles
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Cacquevel, Matthias
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Schneider, Bernard L.
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Aebischer, Patrick
0451562c-5936-4c53-b1e4-56abcfe73f62
Wouters, Fred S.
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Richardson, Jill C.
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Hussain, Ishrut
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Howlett, David R.
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Spillantini, Maria Grazia
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Fawcett, James W.
4549730e-9f62-45b8-820b-8a9c98d1058b
Dassie, Elisa
18566ce2-048b-47b8-928b-1c2baccf149a
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Bensadoun, Jean-Charles
ab674192-ac7d-4df8-94e6-3a7ed98cb115
Cacquevel, Matthias
7ae6bea0-6db7-41c0-8428-455718918d51
Schneider, Bernard L.
52cfe376-89b2-4ad1-a9c6-90a65c9bdca1
Aebischer, Patrick
0451562c-5936-4c53-b1e4-56abcfe73f62
Wouters, Fred S.
8f29f358-82af-420a-bdf3-bb52dfe9007c
Richardson, Jill C.
d7a70bf0-c0d5-480a-857f-1f126c5aa0cb
Hussain, Ishrut
c3c640ea-9cbe-420c-bb16-046ad84d8211
Howlett, David R.
6b42fb1e-e03f-48eb-91ca-c22fdb78e4d8
Spillantini, Maria Grazia
33bc74d0-8e18-47a9-850a-c65fcbe76ff7
Fawcett, James W.
4549730e-9f62-45b8-820b-8a9c98d1058b

Dassie, Elisa, Andrews, Melissa R., Bensadoun, Jean-Charles, Cacquevel, Matthias, Schneider, Bernard L., Aebischer, Patrick, Wouters, Fred S., Richardson, Jill C., Hussain, Ishrut, Howlett, David R., Spillantini, Maria Grazia and Fawcett, James W. (2013) Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model. Neurobiology of Aging, 34 (5), 1355-68. (doi:10.1016/j.neurobiolaging.2012.11.011).

Record type: Article

Abstract

Adeno-associated virus serotype 6 (AAV6) viral vectors encoding mutant and normal tau were used to produce focal tau pathology. Two mutant forms of tau were used; the P301S tau mutation is associated with neurofibrillary tangle formation in humans, and the 3PO mutation leads to rapid tau aggregation and is associated with pathogenic phosphorylation and cytotoxicity in vitro. We show that adeno-associated viral injection into entorhinal cortex of normal and tau knockout animals leads to local overexpression of tau, and the presence of human tau in axons projecting to and emanating from the entorhinal cortex. Starting at 2 months and increasing by 6 months post-injection neurons expressing mutant tau developed hyperphosphorylated tau pathology, in addition to dystrophic neurites. There was neuronal loss in tau-expressing regions, which was similar in normal and in TASTPM mice injected with mutant tau. There was neuroinflammation around plaques, and in regions expressing mutant tau. We saw no evidence that mutant tau had affected amyloid-beta pathology or vice versa. Morris water maze behavioral tests demonstrated mild memory impairment attributable to amyloid-beta pathology at 2 and 4 months, with severe impairment at 6 months in animals receiving adeno-associated viral-3PO. Therefore, TASTPM mice injected with mutant tau displayed many of the main features characteristic of human Alzheimer's disease patients and might be used as a model to test new drugs to ameliorate clinical features of Alzheimer's disease.

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More information

Published date: May 2013
Additional Information: Copyright © 2013 Elsevier Inc. All rights reserved.
Keywords: Alzheimer's Disease, Adeno-associated virus, Alzheimer's precursor protein, tau, tauopathy, viral vectors, memory, neurodegeneraation
Organisations: Biomedicine

Identifiers

Local EPrints ID: 411076
URI: https://eprints.soton.ac.uk/id/eprint/411076
PURE UUID: 1e68cd25-7268-49d0-819a-2b46741f3299
ORCID for Melissa R. Andrews: ORCID iD orcid.org/0000-0001-5960-5619

Catalogue record

Date deposited: 13 Jun 2017 16:33
Last modified: 20 Jul 2019 00:28

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Contributors

Author: Elisa Dassie
Author: Jean-Charles Bensadoun
Author: Matthias Cacquevel
Author: Bernard L. Schneider
Author: Patrick Aebischer
Author: Fred S. Wouters
Author: Jill C. Richardson
Author: Ishrut Hussain
Author: David R. Howlett
Author: Maria Grazia Spillantini
Author: James W. Fawcett

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