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

• Published in: Molecular Neurodegeneration
• Main Authors: 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, Nguyen, Hoang, 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, Gnörich, 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.
• Format: Text
• Language: English
• Published: BioMed Central 2022
• Subjects: Research Article; Arctic
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188195/; http://www.ncbi.nlm.nih.gov/pubmed/35690868; https://doi.org/10.1186/s13024-022-00547-7

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 ...