Comprehensive analysis of microglia across neuropathological stages of Alzheimer's disease (AD) Kelly R. Miller1,2, Stefan Prokop1, Sergio Rodriguez Labra1, Rose M. Pitkin1, Edward B. Lee1, Virginia M.-Y. Lee1, John Q. Trojanowski1. 1AD Center Core (ADCC), Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania (PENN) School of Medicine, Philadelphia, PA 19104, USA 2present address: Nanostring Technologies, Seattle, WA 98109, USA
The pathognomonic protein deposits in AD elicit an activation of microglia, but the role of this innate immune activation in the course of AD is controversial, in part because mouse models of AD pathology do not fully capture the complex human disease condition. To tackle this problem, we undertook a comprehensive analysis of microglia in different stages of AD in human brains to lay the groundwork for mapping the innate immune response towards extracellular and intracellular pathologies in human neurodegenerative disease. Morphologic characterization of microglia in different stages of AD using immunohistochemical (IHC) markers revealed increased microglial activation with advancement of AD neuropathological changes and an increase in dystrophic microglia in late disease stages. Our immunohistochemical findings were corroborated with cell type and pathway specific gene expression profiling using the human Neuropathology gene expression panel on the Nanonstring nCounter system, which demonstrated an increase in microglial activation with progression of AD neuropathological changes. This analysis also revealed distinct differences in gene expression profiles derived from patient samples carrying an AD associated risk variant of the microglia receptor Trem2. We further homed in on these differences by using the nCounter human Neuroinflammation panel to elucidate differentially regulated pathways in AD patients carrying Trem2 risk variants in comparison to disease stage matched patients with a normal variant of Trem2. Our studies demonstrate that combining morphologic characterization of microglia cells with novel cell type and pathway specific gene expression analysis in human post mortem brain specimens allows for interrogation of the innate immune system in the complex environment of a coexisting multitude of different protein pathologies in AD and provides novel insight into the role of the immune system in AD pathogenesis and progression.
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