Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those model...
Published in: | Molecular Neurodegeneration |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
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Biomed Central
2022
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Online Access: | https://pub.dzne.de/record/164831 https://pub.dzne.de/search?p=id:%22DZNE-2022-01275%22 |
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ftdznevdb:oai:pub.dzne.de:164831 |
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openpolar |
institution |
Open Polar |
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DZNEPUB (German Center for Neurodegenerative Diseases) |
op_collection_id |
ftdznevdb |
language |
English |
topic |
info:eu-repo/classification/ddc/570 Alzheimer Disease: genetics Alzheimer Disease: metabolism Amyloid beta-Peptides: metabolism Amyloid beta-Protein Precursor: genetics Amyloid beta-Protein Precursor: metabolism Amyloidosis: metabolism Animals Brain: metabolism Disease Models Animal Mice Transgenic Microglia: metabolism Plaque Amyloid: pathology Receptors GABA: metabolism |
spellingShingle |
info:eu-repo/classification/ddc/570 Alzheimer Disease: genetics Alzheimer Disease: metabolism Amyloid beta-Peptides: metabolism Amyloid beta-Protein Precursor: genetics Amyloid beta-Protein Precursor: metabolism Amyloidosis: metabolism Animals Brain: metabolism Disease Models Animal Mice Transgenic Microglia: metabolism Plaque Amyloid: pathology Receptors GABA: metabolism Xia, Dan Lianoglou, Steve Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Nguyen, Hoang Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Sandmann, Thomas Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Calvert, Meredith Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnoerich, Johannes Wind, Karin Lea, Kunze Zatcepin, Artem Brendel, Matthias Willem, Michael Suh, Jung H. Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
topic_facet |
info:eu-repo/classification/ddc/570 Alzheimer Disease: genetics Alzheimer Disease: metabolism Amyloid beta-Peptides: metabolism Amyloid beta-Protein Precursor: genetics Amyloid beta-Protein Precursor: metabolism Amyloidosis: metabolism Animals Brain: metabolism Disease Models Animal Mice Transgenic Microglia: metabolism Plaque Amyloid: pathology Receptors GABA: metabolism |
description |
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.Methods: We engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.Results: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a ... |
format |
Article in Journal/Newspaper |
author |
Xia, Dan Lianoglou, Steve Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Nguyen, Hoang Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Sandmann, Thomas Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Calvert, Meredith Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnoerich, Johannes Wind, Karin Lea, Kunze Zatcepin, Artem Brendel, Matthias Willem, Michael Suh, Jung H. Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. |
author_facet |
Xia, Dan Lianoglou, Steve Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Nguyen, Hoang Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Sandmann, Thomas Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Calvert, Meredith Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnoerich, Johannes Wind, Karin Lea, Kunze Zatcepin, Artem Brendel, Matthias Willem, Michael Suh, Jung H. Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. |
author_sort |
Xia, Dan |
title |
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
title_short |
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
title_full |
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
title_fullStr |
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
title_full_unstemmed |
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
title_sort |
novel app knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
publisher |
Biomed Central |
publishDate |
2022 |
url |
https://pub.dzne.de/record/164831 https://pub.dzne.de/search?p=id:%22DZNE-2022-01275%22 |
op_coverage |
DE |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Molecular neurodegeneration 17(1), 41 (2022). doi:10.1186/s13024-022-00547-7 |
op_relation |
info:eu-repo/semantics/altIdentifier/issn/1750-1326 info:eu-repo/semantics/altIdentifier/pmid/pmid:35690868 info:eu-repo/semantics/altIdentifier/doi/10.1186/s13024-022-00547-7 https://pub.dzne.de/record/164831 https://pub.dzne.de/search?p=id:%22DZNE-2022-01275%22 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1186/s13024-022-00547-7 |
container_title |
Molecular Neurodegeneration |
container_volume |
17 |
container_issue |
1 |
_version_ |
1779312543865503744 |
spelling |
ftdznevdb:oai:pub.dzne.de:164831 2023-10-09T21:49:31+02:00 Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia Xia, Dan Lianoglou, Steve Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Nguyen, Hoang Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Sandmann, Thomas Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Calvert, Meredith Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnoerich, Johannes Wind, Karin Lea, Kunze Zatcepin, Artem Brendel, Matthias Willem, Michael Suh, Jung H. Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. DE 2022 https://pub.dzne.de/record/164831 https://pub.dzne.de/search?p=id:%22DZNE-2022-01275%22 eng eng Biomed Central info:eu-repo/semantics/altIdentifier/issn/1750-1326 info:eu-repo/semantics/altIdentifier/pmid/pmid:35690868 info:eu-repo/semantics/altIdentifier/doi/10.1186/s13024-022-00547-7 https://pub.dzne.de/record/164831 https://pub.dzne.de/search?p=id:%22DZNE-2022-01275%22 info:eu-repo/semantics/openAccess Molecular neurodegeneration 17(1), 41 (2022). doi:10.1186/s13024-022-00547-7 info:eu-repo/classification/ddc/570 Alzheimer Disease: genetics Alzheimer Disease: metabolism Amyloid beta-Peptides: metabolism Amyloid beta-Protein Precursor: genetics Amyloid beta-Protein Precursor: metabolism Amyloidosis: metabolism Animals Brain: metabolism Disease Models Animal Mice Transgenic Microglia: metabolism Plaque Amyloid: pathology Receptors GABA: metabolism info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2022 ftdznevdb https://doi.org/10.1186/s13024-022-00547-7 2023-09-21T07:38:06Z Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.Methods: We engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.Results: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a ... Article in Journal/Newspaper Arctic DZNEPUB (German Center for Neurodegenerative Diseases) Arctic Molecular Neurodegeneration 17 1 |