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

Mol Neurodegener. 2022 Jun 11;17(1):41. doi: 10.1186/s13024-022-00547-7. PMID: 35690868; PMCID: PMC9188195.

Authors/Editors: Xia D, Lianoglou S, Sandmann T, Calvert M, Suh JH, Thomsen E, Dugas J, Pizzo ME, DeVos SL, Earr TK, Lin CC, Davis S, Ha C, Leung AW, Nguyen H, Chau R, Yulyaningsih E, Lopez I, Solanoy H, Solanoy H, Masoud ST, Liang CC, Lin K, Astarita G, Khoury N, Zuchero JY, Thorne RG, Shen K, Miller S, Palop JJ, Garceau D, Sasner M, Whitesell JD, Harris JA, Hummel S, Gnörich J, Wind K, Kunze L, Zatcepin A, Brendel M, Willem M, Haass C, Barnett D, Zimmer TS, Orr AG, Scearce-Levie K, Lewcock JW, Di Paolo G, Sanchez PE.
Publication Date: 2022

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.

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