Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease
| Autor: | Levi B. Wood, Hailian Xiao, Supriya Ramesha, Srikant Rangaraju, Laura D. Weinstock, Eric B. Dammer, James J. Lah, Duc D Duong, Nicholas T. Seyfried, Lingyan Ping, Michael J. Chen, Tianwen Gao, Allan I. Levey |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway MAP Kinase Signaling System Primary Cell Culture Regulator Gene Expression Biology Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Phagocytosis Alzheimer Disease medicine Animals Phosphorylation Protein kinase A Neuroinflammation Amyloid beta-Peptides Microglia TREM2 Kinase Cell biology 030104 developmental biology medicine.anatomical_structure Female Transcriptome 030217 neurology & neurosurgery |
| Zdroj: | J Neurosci Res |
| ISSN: | 1097-4547 0360-4012 |
| Popis: | 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-β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ-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 post-mortem 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. |
| Databáze: | OpenAIRE |
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