Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 99, Issue 6, Pages 1704-1721Publisher
WILEY
DOI: 10.1002/jnr.24829
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Funding
- Georgia Clinical and Translational Science Alliance [UL1TR002378]
- National Institute of Biomedical Imaging and Bioengineering [T32-GM008433]
- Georgia Institute of Technology
- Alzheimer's Disease Research Center, Emory University [P50 AG025688, P30 AG066511]
- National Science Foundation CBET/EBS Program [1944053]
- National Institutes of Health [K08-NS099474-1, 1R01NS114130-01A1]
- Alzheimer's Association [AARG 37102]
- Accelerating Medicine Partnership for Alzheimer's Disease [U01 AG046161, U01 AG061357]
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1944053] Funding Source: National Science Foundation
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The study indicates that phosphorylation of ERK signaling pathway in microglia is a crucial regulator of pro-inflammatory immune responses in AD pathogenesis, and is also involved in the modulation of disease-associated genes.
The importance of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid-beta and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFN gamma-mediated pro-inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho-ERK was an upstream regulator of disease-associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro-inflammatory immune responses in AD pathogenesis.
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