Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model

Xia, D.; Lianoglou, S.; Sandmann, T.; Calvert, M.; Suh, J. H.; Thomsen, E.; Dugas, J.; Pizzo, M. E.; DeVos, S. L.; Earr, T. K.; Lin, C.-C.; Davis, S.; Ha, C.; Nguyen, H.; Chau, R.; Yulyaningsih, E.; Solanoy, H.; Masoud, S. T.; Liang, R.; Lin, K.; Thorne, R. G.; Garceau, D.; Whitesell, J. D.; Sasner, M.; Harris, J. A.; Scearce-Levie, K.; Lewcock, J. W.; Paolo, G. D.; Sanchez, P. E.

doi:10.1101/2021.01.19.426731

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bioRxiv · 10.1101/2021.01.19.426731

Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model

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Abstract

Microglial dysfunction is believed to play a pathogenic role in Alzheimers disease (AD). Here, we characterize the amyloid-{beta} related pathology and microglial responses in an engineered APP knock-in mouse model of familial AD. This model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered glial responses and neurodegeneration. Leveraging multi-omics approaches, we found lipid accumulation and an exacerbated disease-associated transcriptomic response in methoxy-X04-positive, phagocytic microglia. Together, these findings highlight the potential of this novel, open-access mouse model to investigate AD pathogenesis and demonstrate that fibrillar A{beta} triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia. HighlightsO_LINovel open-access APP KI mouse model shows salient AD pathological features C_LIO_LIDeep phenotyping of sorted microglia reveals profound lipidomic perturbations in line with Alois Alzheimers original descriptions of glial adipose inclusions C_LIO_LIImmunometabolic perturbations are exacerbated in microglia accumulating fibrillar A{beta} C_LI

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Xia, D., Lianoglou, S., Sandmann, T., Calvert, M., Suh, J. H., Thomsen, E., Dugas, J., Pizzo, M. E., DeVos, S. L., Earr, T. K., Lin, C.-C., Davis, S., Ha, C., Nguyen, H., Chau, R., Yulyaningsih, E., Solanoy, H., Masoud, S. T., Liang, R., Lin, K., Thorne, R. G., Garceau, D., Whitesell, J. D., Sasner, M., Harris, J. A., Scearce-Levie, K., Lewcock, J. W., Paolo, G. D., Sanchez, P. E.. 2021-01-20. Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model. https://doi.org/10.1101/2021.01.19.426731

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