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
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
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.
- 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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