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Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models

In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent sprea...

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Autores principales: Sankaranarayanan, Sethu, Barten, Donna M., Vana, Laurel, Devidze, Nino, Yang, Ling, Cadelina, Gregory, Hoque, Nina, DeCarr, Lynn, Keenan, Stefanie, Lin, Alan, Cao, Yang, Snyder, Bradley, Zhang, Bin, Nitla, Magdalena, Hirschfeld, Gregg, Barrezueta, Nestor, Polson, Craig, Wes, Paul, Rangan, Vangipuram S., Cacace, Angela, Albright, Charles F., Meredith, Jere, Trojanowski, John Q., Lee, Virginia M-Y., Brunden, Kurt R., Ahlijanian, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416899/
https://www.ncbi.nlm.nih.gov/pubmed/25933020
http://dx.doi.org/10.1371/journal.pone.0125614
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author Sankaranarayanan, Sethu
Barten, Donna M.
Vana, Laurel
Devidze, Nino
Yang, Ling
Cadelina, Gregory
Hoque, Nina
DeCarr, Lynn
Keenan, Stefanie
Lin, Alan
Cao, Yang
Snyder, Bradley
Zhang, Bin
Nitla, Magdalena
Hirschfeld, Gregg
Barrezueta, Nestor
Polson, Craig
Wes, Paul
Rangan, Vangipuram S.
Cacace, Angela
Albright, Charles F.
Meredith, Jere
Trojanowski, John Q.
Lee, Virginia M-Y.
Brunden, Kurt R.
Ahlijanian, Michael
author_facet Sankaranarayanan, Sethu
Barten, Donna M.
Vana, Laurel
Devidze, Nino
Yang, Ling
Cadelina, Gregory
Hoque, Nina
DeCarr, Lynn
Keenan, Stefanie
Lin, Alan
Cao, Yang
Snyder, Bradley
Zhang, Bin
Nitla, Magdalena
Hirschfeld, Gregg
Barrezueta, Nestor
Polson, Craig
Wes, Paul
Rangan, Vangipuram S.
Cacace, Angela
Albright, Charles F.
Meredith, Jere
Trojanowski, John Q.
Lee, Virginia M-Y.
Brunden, Kurt R.
Ahlijanian, Michael
author_sort Sankaranarayanan, Sethu
collection PubMed
description In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.
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spelling pubmed-44168992015-05-07 Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models Sankaranarayanan, Sethu Barten, Donna M. Vana, Laurel Devidze, Nino Yang, Ling Cadelina, Gregory Hoque, Nina DeCarr, Lynn Keenan, Stefanie Lin, Alan Cao, Yang Snyder, Bradley Zhang, Bin Nitla, Magdalena Hirschfeld, Gregg Barrezueta, Nestor Polson, Craig Wes, Paul Rangan, Vangipuram S. Cacace, Angela Albright, Charles F. Meredith, Jere Trojanowski, John Q. Lee, Virginia M-Y. Brunden, Kurt R. Ahlijanian, Michael PLoS One Research Article In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies. Public Library of Science 2015-05-01 /pmc/articles/PMC4416899/ /pubmed/25933020 http://dx.doi.org/10.1371/journal.pone.0125614 Text en © 2015 Sankaranarayanan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sankaranarayanan, Sethu
Barten, Donna M.
Vana, Laurel
Devidze, Nino
Yang, Ling
Cadelina, Gregory
Hoque, Nina
DeCarr, Lynn
Keenan, Stefanie
Lin, Alan
Cao, Yang
Snyder, Bradley
Zhang, Bin
Nitla, Magdalena
Hirschfeld, Gregg
Barrezueta, Nestor
Polson, Craig
Wes, Paul
Rangan, Vangipuram S.
Cacace, Angela
Albright, Charles F.
Meredith, Jere
Trojanowski, John Q.
Lee, Virginia M-Y.
Brunden, Kurt R.
Ahlijanian, Michael
Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models
title Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models
title_full Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models
title_fullStr Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models
title_full_unstemmed Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models
title_short Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models
title_sort passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416899/
https://www.ncbi.nlm.nih.gov/pubmed/25933020
http://dx.doi.org/10.1371/journal.pone.0125614
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