Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
Abstract 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 disea...
Published in: | Molecular Neurodegeneration |
---|---|
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
BMC
2022
|
Subjects: | |
Online Access: | https://doi.org/10.1186/s13024-022-00547-7 https://doaj.org/article/9eb417ef38964cb082e476c72c827f5f |
id |
ftdoajarticles:oai:doaj.org/article:9eb417ef38964cb082e476c72c827f5f |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:9eb417ef38964cb082e476c72c827f5f 2023-05-15T15:15:48+02:00 Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia Dan Xia Steve Lianoglou Thomas Sandmann Meredith Calvert Jung H. Suh Elliot Thomsen Jason Dugas Michelle E. Pizzo Sarah L. DeVos Timothy K. Earr Chia-Ching Lin Sonnet Davis Connie Ha Amy Wing-Sze Leung Hoang Nguyen Roni Chau Ernie Yulyaningsih Isabel Lopez Hilda Solanoy Shababa T. Masoud Chun-chi Liang Karin Lin Giuseppe Astarita Nathalie Khoury Joy Yu Zuchero Robert G. Thorne Kevin Shen Stephanie Miller Jorge J. Palop Dylan Garceau Michael Sasner Jennifer D. Whitesell Julie A. Harris Selina Hummel Johannes Gnörich Karin Wind Lea Kunze Artem Zatcepin Matthias Brendel Michael Willem Christian Haass Daniel Barnett Till S. Zimmer Anna G. Orr Kimberly Scearce-Levie Joseph W. Lewcock Gilbert Di Paolo Pascal E. Sanchez 2022-06-01T00:00:00Z https://doi.org/10.1186/s13024-022-00547-7 https://doaj.org/article/9eb417ef38964cb082e476c72c827f5f EN eng BMC https://doi.org/10.1186/s13024-022-00547-7 https://doaj.org/toc/1750-1326 doi:10.1186/s13024-022-00547-7 1750-1326 https://doaj.org/article/9eb417ef38964cb082e476c72c827f5f Molecular Neurodegeneration, Vol 17, Iss 1, Pp 1-29 (2022) Neuritic plaques Vascular amyloid Neurodegeneration Astrogliosis Phagocytic microglia Lipid dyshomeostasis Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6 article 2022 ftdoajarticles https://doi.org/10.1186/s13024-022-00547-7 2022-12-31T02:34:30Z Abstract 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-β 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 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 App SAA knock-in mouse model recapitulates key pathological features ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Molecular Neurodegeneration 17 1 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Neuritic plaques Vascular amyloid Neurodegeneration Astrogliosis Phagocytic microglia Lipid dyshomeostasis Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6 |
spellingShingle |
Neuritic plaques Vascular amyloid Neurodegeneration Astrogliosis Phagocytic microglia Lipid dyshomeostasis Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6 Dan Xia Steve Lianoglou Thomas Sandmann Meredith Calvert Jung H. Suh Elliot Thomsen Jason Dugas Michelle E. Pizzo Sarah L. DeVos Timothy K. Earr Chia-Ching Lin Sonnet Davis Connie Ha Amy Wing-Sze Leung Hoang Nguyen Roni Chau Ernie Yulyaningsih Isabel Lopez Hilda Solanoy Shababa T. Masoud Chun-chi Liang Karin Lin Giuseppe Astarita Nathalie Khoury Joy Yu Zuchero Robert G. Thorne Kevin Shen Stephanie Miller Jorge J. Palop Dylan Garceau Michael Sasner Jennifer D. Whitesell Julie A. Harris Selina Hummel Johannes Gnörich Karin Wind Lea Kunze Artem Zatcepin Matthias Brendel Michael Willem Christian Haass Daniel Barnett Till S. Zimmer Anna G. Orr Kimberly Scearce-Levie Joseph W. Lewcock Gilbert Di Paolo Pascal E. Sanchez Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia |
topic_facet |
Neuritic plaques Vascular amyloid Neurodegeneration Astrogliosis Phagocytic microglia Lipid dyshomeostasis Neurology. Diseases of the nervous system RC346-429 Geriatrics RC952-954.6 |
description |
Abstract 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-β 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 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 App SAA knock-in mouse model recapitulates key pathological features ... |
format |
Article in Journal/Newspaper |
author |
Dan Xia Steve Lianoglou Thomas Sandmann Meredith Calvert Jung H. Suh Elliot Thomsen Jason Dugas Michelle E. Pizzo Sarah L. DeVos Timothy K. Earr Chia-Ching Lin Sonnet Davis Connie Ha Amy Wing-Sze Leung Hoang Nguyen Roni Chau Ernie Yulyaningsih Isabel Lopez Hilda Solanoy Shababa T. Masoud Chun-chi Liang Karin Lin Giuseppe Astarita Nathalie Khoury Joy Yu Zuchero Robert G. Thorne Kevin Shen Stephanie Miller Jorge J. Palop Dylan Garceau Michael Sasner Jennifer D. Whitesell Julie A. Harris Selina Hummel Johannes Gnörich Karin Wind Lea Kunze Artem Zatcepin Matthias Brendel Michael Willem Christian Haass Daniel Barnett Till S. Zimmer Anna G. Orr Kimberly Scearce-Levie Joseph W. Lewcock Gilbert Di Paolo Pascal E. Sanchez |
author_facet |
Dan Xia Steve Lianoglou Thomas Sandmann Meredith Calvert Jung H. Suh Elliot Thomsen Jason Dugas Michelle E. Pizzo Sarah L. DeVos Timothy K. Earr Chia-Ching Lin Sonnet Davis Connie Ha Amy Wing-Sze Leung Hoang Nguyen Roni Chau Ernie Yulyaningsih Isabel Lopez Hilda Solanoy Shababa T. Masoud Chun-chi Liang Karin Lin Giuseppe Astarita Nathalie Khoury Joy Yu Zuchero Robert G. Thorne Kevin Shen Stephanie Miller Jorge J. Palop Dylan Garceau Michael Sasner Jennifer D. Whitesell Julie A. Harris Selina Hummel Johannes Gnörich Karin Wind Lea Kunze Artem Zatcepin Matthias Brendel Michael Willem Christian Haass Daniel Barnett Till S. Zimmer Anna G. Orr Kimberly Scearce-Levie Joseph W. Lewcock Gilbert Di Paolo Pascal E. Sanchez |
author_sort |
Dan Xia |
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 |
BMC |
publishDate |
2022 |
url |
https://doi.org/10.1186/s13024-022-00547-7 https://doaj.org/article/9eb417ef38964cb082e476c72c827f5f |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Molecular Neurodegeneration, Vol 17, Iss 1, Pp 1-29 (2022) |
op_relation |
https://doi.org/10.1186/s13024-022-00547-7 https://doaj.org/toc/1750-1326 doi:10.1186/s13024-022-00547-7 1750-1326 https://doaj.org/article/9eb417ef38964cb082e476c72c827f5f |
op_doi |
https://doi.org/10.1186/s13024-022-00547-7 |
container_title |
Molecular Neurodegeneration |
container_volume |
17 |
container_issue |
1 |
_version_ |
1766346139238400000 |