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Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements

Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements
Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements
Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia.
tau, p310l, tangles, transgenic mice, immunization, behaviour
9115-9129
Asuni, A.A.
b1412b1b-9794-4705-aada-aed5d3da038f
Boutajangout, A.
a8357b95-0a97-421e-be7b-ff2bb22e8418
Quartermain, D.
2a73f179-4710-4861-8ebc-33d08fd9d22b
Sigurdsson, E.M.
9e00ebbc-aec3-4fd2-a4e1-f0696f5fbf00
Asuni, A.A.
b1412b1b-9794-4705-aada-aed5d3da038f
Boutajangout, A.
a8357b95-0a97-421e-be7b-ff2bb22e8418
Quartermain, D.
2a73f179-4710-4861-8ebc-33d08fd9d22b
Sigurdsson, E.M.
9e00ebbc-aec3-4fd2-a4e1-f0696f5fbf00

Asuni, A.A., Boutajangout, A., Quartermain, D. and Sigurdsson, E.M. (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. Journal of Neuroscience, 27 (34), 9115-9129. (doi:10.1523/Jneurosci.2361-07.2007).

Record type: Article

Abstract

Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia.

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More information

Published date: 22 August 2007
Keywords: tau, p310l, tangles, transgenic mice, immunization, behaviour
Organisations: Centre for Biological Sciences

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Local EPrints ID: 345519
URI: https://eprints.soton.ac.uk/id/eprint/345519
PURE UUID: bdc1154f-7402-4475-a8cd-bdbaa58e646d

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Date deposited: 12 Feb 2013 15:11
Last modified: 18 Jul 2017 05:09

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Contributors

Author: A.A. Asuni
Author: A. Boutajangout
Author: D. Quartermain
Author: E.M. Sigurdsson

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