Dan Xia, United States of America
Denali Therapeutics Translational SciencesAuthor Of 1 Presentation
NOVEL APP KNOCK-IN MOUSE MODEL REVEALS PROFOUND METABOLIC PERTURBATIONS IN PHAGOCYTIC MICROGLIA
Abstract
Aims
Emerging human genetics and preclinical research revealed that microglia are likely contributing to AD pathophysiology. Microglia are responding to various pathogenic drivers of AD but the mechanisms by which microglia become dysfunctional and contribute to disease remain unclear. Here, we aimed to characterize amyloid-β related pathology and microglial responses in a novel APP knock-in mouse model. In particular, we sought to determine if pathogenic fibrillar form of Aβ causes transcriptomic and lipid dysregulation in microglia as a result of phagocytic uptake and to which extent this dysregulation perturbs immunometabolism.
Methods
We developed and characterized a new APP knock-in (KI) mouse model that circumvent limitations of transgenesis and applied multi-omics approaches in combination with cell population enrichment techniques to deeply characterize cellular perturbations of microglia in this mouse model.
Results
We validated the novel APP-KI mouse model by showing a dramatic increase of Aβ42/40 ratio in the brain, CSF and plasma at various ages, and demonstrated that it was associated with a progressive accumulation of amyloid plaques and an increase of markers of neuroinflammation and neurodegeneration. We then describe profound transcriptomic and lipidomic perturbations in brain-sorted microglia and reveal that some of those changes were exacerbated or unique in microglia showing evidence of Aβ accumulation.
Conclusions
Our in-depth analysis of this novel APP KI mouse model confirms emergence of disease-relevant biology and progressive accumulation of pathological hallmarks of AD. Additionally, we reveal profound immunometabolic perturbations in microglia supporting the notion that profound cellular alterations may lead to lysosomal dysfunction in highly phagocytic microglia.