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Author Notes:

Corresponding author: Srikant Rangaraju, Email:srikant.rangaraju@emory.edu

Conceptualization: SR, EBD, SAR, NTS and AIL; Methodology: SR, EBD, SAR, NTS, AIL;

Investigation: SR, EBD, SAR, DD, CMH, TG, JW, HX, PR and HX;

Writing-Original draft: SR, EBD;

Writing-Review and Editing: SR, EBD, SAR, CMH, AIL, JJL, RB, NTS

Funding Acquisition: SR, AIL, NTS; Resources: AIL, NTS, JJL

Supervision: AIL, NTS.

All authors have approved of the contents of this manuscript and provided consent for publication.

Srikant Rangaraju and Eric B. Dammer contributed equally to this work.

Approval from the Emory University Institutional Animal Care and Use Committee was obtained prior to all animal-related studies (IACUC protocol # 300123).

The authors declare that they have no competing interests.

Subjects:

Research Funding:

Work supported by Emory Alzheimer’s Disease Research Center Grant P50 AG025688, American Brain Foundation (SR #28301), Alzheimer’s Association (SR #37102), NINDS (SR: K08-NS099474–1; CMH: K08-NS087121) and Emory Neuroscience NINDS Core facilities (P30 NS055077).

Other NIH grants that supported this work include U01AG046161, RF1AG057471, R01AG057330 and RF1AG057470, 5R01AG053960.

NTS was also supported by Alzheimer’s Association grant 11060.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Microglia
  • Neurodegeneration
  • Neuroinflammation
  • Immunology
  • Proteomics
  • Mass spectrometry
  • Alzheimer's disease
  • APOLIPOPROTEIN-E
  • HUMAN BRAIN
  • NETWORK APPROACH
  • GAMMA-SECRETASE
  • BETA
  • PATHWAY
  • NEUROINFLAMMATION
  • DEGRADATION
  • ACTIVATION
  • INSIGHTS

Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer's disease-related proteins

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Journal Title:

Molecular Neurodegeneration

Volume:

Volume 13, Number 1

Publisher:

, Pages 34-34

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: 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 spectrometry 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, comprehensive proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. Methods: We performed quantitative mass spectrometry based proteomic analyses of purified CD11b+acutely-isolated microglia from adult (6 mo) mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer's disease [AD]). 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. Results: Of 4133 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. Conclusions: We report a comprehensive proteomic study of adult mouse microglia derived from acute neuroinflammation and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammation aging and AD mouse models and identify novel roles for microglial proteins in human neurodegeneration.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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