A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide
We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (App(NL-G-F) and App(NL-F) mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impa...
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American Society for Biochemistry and Molecular Biology
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ftpubmed:oai:pubmedcentral.nih.gov:8397900 2023-05-15T14:59:22+02:00 A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide Sato, Kaori Watamura, Naoto Fujioka, Ryo Mihira, Naomi Sekiguchi, Misaki Nagata, Kenichi Ohshima, Toshio Saito, Takashi Saido, Takaomi C. Sasaguri, Hiroki 2021-07-27 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397900/ http://www.ncbi.nlm.nih.gov/pubmed/34329683 https://doi.org/10.1016/j.jbc.2021.101004 en eng American Society for Biochemistry and Molecular Biology http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397900/ http://www.ncbi.nlm.nih.gov/pubmed/34329683 http://dx.doi.org/10.1016/j.jbc.2021.101004 © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). CC-BY J Biol Chem Research Article Text 2021 ftpubmed https://doi.org/10.1016/j.jbc.2021.101004 2021-09-05T00:50:38Z We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (App(NL-G-F) and App(NL-F) mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the App(NL-F) line with the Psen1(P117L/WT) line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new third-generation mouse model showed more cored plaque pathology and neuroinflammation than App(NL-G-F) mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD. Text Arctic PubMed Central (PMC) Arctic Journal of Biological Chemistry 297 3 101004 |
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Research Article Sato, Kaori Watamura, Naoto Fujioka, Ryo Mihira, Naomi Sekiguchi, Misaki Nagata, Kenichi Ohshima, Toshio Saito, Takashi Saido, Takaomi C. Sasaguri, Hiroki A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
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Research Article |
description |
We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (App(NL-G-F) and App(NL-F) mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the App(NL-F) line with the Psen1(P117L/WT) line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new third-generation mouse model showed more cored plaque pathology and neuroinflammation than App(NL-G-F) mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD. |
format |
Text |
author |
Sato, Kaori Watamura, Naoto Fujioka, Ryo Mihira, Naomi Sekiguchi, Misaki Nagata, Kenichi Ohshima, Toshio Saito, Takashi Saido, Takaomi C. Sasaguri, Hiroki |
author_facet |
Sato, Kaori Watamura, Naoto Fujioka, Ryo Mihira, Naomi Sekiguchi, Misaki Nagata, Kenichi Ohshima, Toshio Saito, Takashi Saido, Takaomi C. Sasaguri, Hiroki |
author_sort |
Sato, Kaori |
title |
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
title_short |
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
title_full |
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
title_fullStr |
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
title_full_unstemmed |
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
title_sort |
third-generation mouse model of alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide |
publisher |
American Society for Biochemistry and Molecular Biology |
publishDate |
2021 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397900/ http://www.ncbi.nlm.nih.gov/pubmed/34329683 https://doi.org/10.1016/j.jbc.2021.101004 |
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Arctic |
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Arctic |
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Arctic |
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Arctic |
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J Biol Chem |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397900/ http://www.ncbi.nlm.nih.gov/pubmed/34329683 http://dx.doi.org/10.1016/j.jbc.2021.101004 |
op_rights |
© 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1016/j.jbc.2021.101004 |
container_title |
Journal of Biological Chemistry |
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297 |
container_issue |
3 |
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101004 |
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1766331473264115712 |