JMG, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloidosis, Animals, Brain, Disease Models, Animal, Mice, Mice, Transgenic, Microglia, Plaque, Amyloid, Receptors, GABA
Mol Neurodegener 2022 Jun 11; 17(1):41
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
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
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.
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; and Sanchez, Pascal E, "Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia." (2022). Faculty Research 2022. 156.