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...
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-06-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-022-00547-7 |
| _version_ | 1818207462605455360 |
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| 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 |
| collection | DOAJ |
| 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 of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged. Discussion Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology. |
| first_indexed | 2024-12-12T04:29:18Z |
| format | Article |
| id | doaj.art-9eb417ef38964cb082e476c72c827f5f |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-12T04:29:18Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-9eb417ef38964cb082e476c72c827f5f2022-12-22T00:38:08ZengBMCMolecular Neurodegeneration1750-13262022-06-0117112910.1186/s13024-022-00547-7Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microgliaDan Xia0Steve Lianoglou1Thomas Sandmann2Meredith Calvert3Jung H. Suh4Elliot Thomsen5Jason Dugas6Michelle E. Pizzo7Sarah L. DeVos8Timothy K. Earr9Chia-Ching Lin10Sonnet Davis11Connie Ha12Amy Wing-Sze Leung13Hoang Nguyen14Roni Chau15Ernie Yulyaningsih16Isabel Lopez17Hilda Solanoy18Shababa T. Masoud19Chun-chi Liang20Karin Lin21Giuseppe Astarita22Nathalie Khoury23Joy Yu Zuchero24Robert G. Thorne25Kevin Shen26Stephanie Miller27Jorge J. Palop28Dylan Garceau29Michael Sasner30Jennifer D. Whitesell31Julie A. Harris32Selina Hummel33Johannes Gnörich34Karin Wind35Lea Kunze36Artem Zatcepin37Matthias Brendel38Michael Willem39Christian Haass40Daniel Barnett41Till S. Zimmer42Anna G. Orr43Kimberly Scearce-Levie44Joseph W. Lewcock45Gilbert Di Paolo46Pascal E. Sanchez47Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Gladstone Institute of Neurological DiseaseGladstone Institute of Neurological DiseaseGladstone Institute of Neurological DiseaseThe Jackson LabThe Jackson LabAllen Institute for Brain ScienceAllen Institute for Brain ScienceGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichDepartment of Nuclear Medicine, University Hospital of MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichAppel Alzheimer’s Disease Research Institute, Weill Cornell MedicineAppel Alzheimer’s Disease Research Institute, Weill Cornell MedicineAppel Alzheimer’s Disease Research Institute, Weill Cornell MedicineDenali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.Denali Therapeutics, Inc.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 of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged. Discussion Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.https://doi.org/10.1186/s13024-022-00547-7Neuritic plaquesVascular amyloidNeurodegenerationAstrogliosisPhagocytic microgliaLipid dyshomeostasis |
| spellingShingle | 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 Molecular Neurodegeneration Neuritic plaques Vascular amyloid Neurodegeneration Astrogliosis Phagocytic microglia Lipid dyshomeostasis |
| title | 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_short | 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 |
| topic | Neuritic plaques Vascular amyloid Neurodegeneration Astrogliosis Phagocytic microglia Lipid dyshomeostasis |
| url | https://doi.org/10.1186/s13024-022-00547-7 |
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