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

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2021

bioRxiv. 2021 Jan 19. doi: https://doi.org/10.1101/2021.01.19.426731

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

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, Hoang Nguyen, Roni Chau, Ernie Yulyaningsih, Hilda Solanoy, Shababa T. Masoud, Richard Liang, Karin Lin, Robert G. Thorne, Dylan Garceau, Jennifer D. Whitesell, Michael Sasner, Julie A. Harris, Kimberly Scearce-Levie, Joseph W. Lewcock, Gilbert Di Paolo, Pascal E. Sanchez.

Denali Therapeutics, Inc., 161 Oyster Point Blvd, South San Francisco, California 94080. Department of Pharmaceutics, University of Minnesota, 9-177 Weaver-Densford Hall, 308 Harvard St. SE, Minneapolis, MN 55455. The Jackson Lab, Bar Harbor, Maine. Allen Institute for Brain Science, Seattle, Washington.

Service type: Knock-in mice

Abstract

Microglial dysfunction is believed to play a pathogenic role in Alzheimer’s disease (AD). Here, we characterize the amyloid-β 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 Aβ triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia.

Highlights

  • Novel open-access APP KI mouse model shows salient AD pathological features
  • Deep phenotyping of sorted microglia reveals profound lipidomic perturbations in line with Alois Alzheimer’s original descriptions of glial adipose inclusions
  • Immunometabolic perturbations are exacerbated in microglia accumulating fibrillar Aβ

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