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Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice

Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI(2) gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are th...

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Autores principales: Garringer, Holly J., Murrell, Jill, Sammeta, Neeraja, Gnezda, Anita, Ghetti, Bernardino, Vidal, Ruben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572042/
https://www.ncbi.nlm.nih.gov/pubmed/23418567
http://dx.doi.org/10.1371/journal.pone.0056426
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author Garringer, Holly J.
Murrell, Jill
Sammeta, Neeraja
Gnezda, Anita
Ghetti, Bernardino
Vidal, Ruben
author_facet Garringer, Holly J.
Murrell, Jill
Sammeta, Neeraja
Gnezda, Anita
Ghetti, Bernardino
Vidal, Ruben
author_sort Garringer, Holly J.
collection PubMed
description Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI(2) gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI(2) (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI(2) can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration.
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spelling pubmed-35720422013-02-15 Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice Garringer, Holly J. Murrell, Jill Sammeta, Neeraja Gnezda, Anita Ghetti, Bernardino Vidal, Ruben PLoS One Research Article Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI(2) gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI(2) (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI(2) can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration. Public Library of Science 2013-02-13 /pmc/articles/PMC3572042/ /pubmed/23418567 http://dx.doi.org/10.1371/journal.pone.0056426 Text en © 2013 Garringer 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
Garringer, Holly J.
Murrell, Jill
Sammeta, Neeraja
Gnezda, Anita
Ghetti, Bernardino
Vidal, Ruben
Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice
title Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice
title_full Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice
title_fullStr Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice
title_full_unstemmed Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice
title_short Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI(2)/Tau Transgenic Mice
title_sort increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant bri(2)/tau transgenic mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572042/
https://www.ncbi.nlm.nih.gov/pubmed/23418567
http://dx.doi.org/10.1371/journal.pone.0056426
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