Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
Background 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,...
Published in: | Molecular Neurodegeneration |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Ludwig-Maximilians-Universität München
2022
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Online Access: | https://epub.ub.uni-muenchen.de/115061/1/s13024-022-00547-7.pdf https://epub.ub.uni-muenchen.de/115061/ http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-115061-2 https://doi.org/10.1186/s13024-022-00547-7 |
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Medizin Munich Cluster for Systems Neurology (SyNergy) ddc:610 |
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Medizin Munich Cluster for Systems Neurology (SyNergy) ddc:610 Xia, Dan Lianoglou, Steve Sandmann, Thomas Calvert, Meredith Suh, Jung H. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Hoang, Nguyen Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnorich, Johannes Wind, Karin Kunze, Lea Zatcepin, Artem Brendel, Matthias Willem, Michael Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
topic_facet |
Medizin Munich Cluster for Systems Neurology (SyNergy) ddc:610 |
description |
Background 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 (App(SAA)) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-beta pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous App(SAA) 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 A beta 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 A beta content. The App(SAA) knock-in mouse model recapitulates key pathological ... |
format |
Article in Journal/Newspaper |
author |
Xia, Dan Lianoglou, Steve Sandmann, Thomas Calvert, Meredith Suh, Jung H. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Hoang, Nguyen Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnorich, Johannes Wind, Karin Kunze, Lea Zatcepin, Artem Brendel, Matthias Willem, Michael Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. |
author_facet |
Xia, Dan Lianoglou, Steve Sandmann, Thomas Calvert, Meredith Suh, Jung H. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Hoang, Nguyen Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnorich, Johannes Wind, Karin Kunze, Lea Zatcepin, Artem Brendel, Matthias Willem, Michael Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. |
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 |
Ludwig-Maximilians-Universität München |
publishDate |
2022 |
url |
https://epub.ub.uni-muenchen.de/115061/1/s13024-022-00547-7.pdf https://epub.ub.uni-muenchen.de/115061/ http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-115061-2 https://doi.org/10.1186/s13024-022-00547-7 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Molecular Neurodegeneration |
op_relation |
Xia, Dan; Lianoglou, Steve; Sandmann, Thomas; Calvert, Meredith; Suh, Jung H.; Thomsen, Elliot; Dugas, Jason; Pizzo, Michelle E.; DeVos, Sarah L.; Earr, Timothy K.; Lin, Chia-Ching; Davis, Sonnet; Ha, Connie; Leung, Amy Wing-Sze; Hoang, Nguyen; Chau, Roni; Yulyaningsih, Ernie; Lopez, Isabel; Solanoy, Hilda; Masoud, Shababa T.; Liang, Chun-chi; Lin, Karin; Astarita, Giuseppe; Khoury, Nathalie; Zuchero, Joy Yu; Thorne, Robert G.; Shen, Kevin; Miller, Stephanie; Palop, Jorge J.; Garceau, Dylan; Sasner, Michael; Whitesell, Jennifer D.; Harris, Julie A.; Hummel, Selina; Gnorich, Johannes; Wind, Karin; Kunze, Lea; Zatcepin, Artem; Brendel, Matthias; Willem, Michael; Haass, Christian; Barnett, Daniel; Zimmer, Till S.; Orr, Anna G.; Scearce-Levie, Kimberly; Lewcock, Joseph W.; Di Paolo, Gilbert und Sanchez, Pascal E. (2022): Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia. In: Molecular Neurodegeneration, Bd. 17, Nr. 1, 41 [PDF, 12MB] https://epub.ub.uni-muenchen.de/115061/1/s13024-022-00547-7.pdf http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-115061-2 https://epub.ub.uni-muenchen.de/115061/ doi:10.1186/s13024-022-00547-7 |
op_doi |
https://doi.org/10.1186/s13024-022-00547-7 |
container_title |
Molecular Neurodegeneration |
container_volume |
17 |
container_issue |
1 |
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1802641791720095744 |
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ftmuenchenepub:oai:epub.ub.uni-muenchen.de:115061 2024-06-23T07:50:51+00:00 Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia Xia, Dan Lianoglou, Steve Sandmann, Thomas Calvert, Meredith Suh, Jung H. Thomsen, Elliot Dugas, Jason Pizzo, Michelle E. DeVos, Sarah L. Earr, Timothy K. Lin, Chia-Ching Davis, Sonnet Ha, Connie Leung, Amy Wing-Sze Hoang, Nguyen Chau, Roni Yulyaningsih, Ernie Lopez, Isabel Solanoy, Hilda Masoud, Shababa T. Liang, Chun-chi Lin, Karin Astarita, Giuseppe Khoury, Nathalie Zuchero, Joy Yu Thorne, Robert G. Shen, Kevin Miller, Stephanie Palop, Jorge J. Garceau, Dylan Sasner, Michael Whitesell, Jennifer D. Harris, Julie A. Hummel, Selina Gnorich, Johannes Wind, Karin Kunze, Lea Zatcepin, Artem Brendel, Matthias Willem, Michael Haass, Christian Barnett, Daniel Zimmer, Till S. Orr, Anna G. Scearce-Levie, Kimberly Lewcock, Joseph W. Di Paolo, Gilbert Sanchez, Pascal E. 2022-01-01 application/pdf https://epub.ub.uni-muenchen.de/115061/1/s13024-022-00547-7.pdf https://epub.ub.uni-muenchen.de/115061/ http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-115061-2 https://doi.org/10.1186/s13024-022-00547-7 eng eng Ludwig-Maximilians-Universität München Xia, Dan; Lianoglou, Steve; Sandmann, Thomas; Calvert, Meredith; Suh, Jung H.; Thomsen, Elliot; Dugas, Jason; Pizzo, Michelle E.; DeVos, Sarah L.; Earr, Timothy K.; Lin, Chia-Ching; Davis, Sonnet; Ha, Connie; Leung, Amy Wing-Sze; Hoang, Nguyen; Chau, Roni; Yulyaningsih, Ernie; Lopez, Isabel; Solanoy, Hilda; Masoud, Shababa T.; Liang, Chun-chi; Lin, Karin; Astarita, Giuseppe; Khoury, Nathalie; Zuchero, Joy Yu; Thorne, Robert G.; Shen, Kevin; Miller, Stephanie; Palop, Jorge J.; Garceau, Dylan; Sasner, Michael; Whitesell, Jennifer D.; Harris, Julie A.; Hummel, Selina; Gnorich, Johannes; Wind, Karin; Kunze, Lea; Zatcepin, Artem; Brendel, Matthias; Willem, Michael; Haass, Christian; Barnett, Daniel; Zimmer, Till S.; Orr, Anna G.; Scearce-Levie, Kimberly; Lewcock, Joseph W.; Di Paolo, Gilbert und Sanchez, Pascal E. (2022): Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia. In: Molecular Neurodegeneration, Bd. 17, Nr. 1, 41 [PDF, 12MB] https://epub.ub.uni-muenchen.de/115061/1/s13024-022-00547-7.pdf http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-115061-2 https://epub.ub.uni-muenchen.de/115061/ doi:10.1186/s13024-022-00547-7 Molecular Neurodegeneration Medizin Munich Cluster for Systems Neurology (SyNergy) ddc:610 doc-type:article Zeitschriftenartikel NonPeerReviewed 2022 ftmuenchenepub https://doi.org/10.1186/s13024-022-00547-7 2024-06-12T01:42:35Z Background 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 (App(SAA)) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-beta pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous App(SAA) 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 A beta 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 A beta content. The App(SAA) knock-in mouse model recapitulates key pathological ... Article in Journal/Newspaper Arctic Open Access LMU (Ludwig-Maximilians-University Munich) Arctic Molecular Neurodegeneration 17 1 |