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Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia

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2022

Mol Neurodegener. 2022 Jun 11;17(1):41. doi: 10.1186/s13024-022-00547-7.

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

Denali Therapeutics, Inc., 161 Oyster Point Blvd, South San Francisco, California, 94080, USA. Department of Pharmaceutics, University of Minnesota, 9-177 Weaver-Densford Hall, 308 Harvard St. SE, Minneapolis, MN, 55455, USA. Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA. Department of Neurology, University of California, San Francisco, CA, 94158, USA. The Jackson Lab, Bar Harbor, Maine, USA. Allen Institute for Brain Science, Seattle, Washington, USA. German Center for Neurodegenerative Diseases (DZNE) Munich, 81377, Munich, Germany. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany. Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig- Maximilians-Universität, München, 81377, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany. Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY, USA. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY, USA.

Service type: Knock-in mice

Abstract

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 (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 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.

Keywords: Astrogliosis; Lipid dyshomeostasis; Neuritic plaques; Neurodegeneration; Phagocytic microglia; Vascular amyloid.

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