Dataset Information

Identification of novel Kv1.3 channel dependent mechanisms in microglial activation

ABSTRACT: Pro-inflammatory microglia contribute to disease progression in neuroinflammatory and neurodegenerative diseases. We identify novel Kv1.3 channel-dependent molecular and cellular mechanisms during microglial activation and unravel a Kv1.3-dependent pathway for MHCI-restricted antigen presentation by microglia to CD8+ T cells.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Microglial Cell

DISEASE(S): Alzheimer's Disease

SUBMITTER: Eric Dammer

LAB HEAD: Nicholas T. Seyfried

PROVIDER: PXD006753 | Pride | 2018-10-24

REPOSITORIES: Pride

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A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation.

Rangaraju Srikant S Raza Syed Ali SA Pennati Andrea A Deng Qiudong Q Dammer Eric B EB Duong Duc D Pennington Michael W MW Tansey Malu G MG Lah James J JJ Betarbet Ranjita R Seyfried Nicholas T NT Levey Allan I AI

Journal of neuroinflammation 20170626 1

<h4>Background</h4>Kv1.3 potassium channels regulate microglial functions and are overexpressed in neuroinflammatory diseases. Kv1.3 blockade may selectively inhibit pro-inflammatory microglia in neurological diseases but the molecular and cellular mechanisms regulated by Kv1.3 channels are poorly defined.<h4>Methods</h4>We performed immunoblotting and flow cytometry to confirm Kv1.3 channel upregulation in lipopolysaccharide (LPS)-activated BV2 microglia and in brain mononuclear phagocytes fres ...[more]

PMID: 28651603

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

			Action	DRS
	Rangaraju-BV2-MaxQuant_TXT_OUTPUT.zip	Other
	UP000000589_10090_mouseUNIPROTsep15withegfp.fasta	Fasta
	sr_04.raw	Raw
	sr_05.raw	Raw
	sr_06.raw	Raw