Flow-cytometric microglial sorting coupled with quantitative proteomics identifies moesin as a highly-abundant microglial protein with relevance to Alzheimer’s disease
Open accessPreprint — published as 10.1186/s13024-020-00377-5 · Paper page
Abstract
Background: Proteomic characterization of microglia provides the most proximate assessment of functionally relevant molecular mechanisms of neuroinflammation. However, microglial proteomics studies have been limited by low cellular yield and contamination by non-microglial proteins using existing enrichment strategies. Methods: We coupled magnetic-activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) of microglia with tandem mass tag-mass spectrometry (TMT-MS) to obtain a highly-pure microglial proteome and identified a core set of highly-abundant microglial proteins in adult mouse brain. We interrogated existing human proteomic data for Alzheimer’s disease (AD) relevance of highly-abundant microglial proteins and performed immuno-histochemical and in-vitro validation studies. Results: Quantitative multiplexed proteomics by TMT-MS of CD11b+ MACS-enriched ( N = 5 mice) and FACS-isolated ( N = 5 mice), from adult wild-type mice, identified 1,791 proteins. A total of 203 proteins were highly abundant in both datasets, representing a core-set of highly abundant microglial proteins. In addition, we found 953 differentially enriched proteins comparing MACS and FACS-based approaches, indicating significant differences between both strategies. The FACS-isolated microglia proteome was enriched with cytosolic, endoplasmic reticulum, and ribosomal proteins involved in protein metabolism and immune system functions, as well as an abundance of canonical microglial proteins. Conversely, the MACS-enriched microglia proteome was enriched with mitochondrial and synaptic proteins and higher abundance of neuronal, oligodendrocytic and astrocytic proteins. From the 203 consensus microglial proteins with high abundance in both datasets, we confirmed microglial expression of moesin (Msn) in wild-type and 5xFAD mouse brains as well as in human AD brains. Msn expression is nearly exclusively found in microglia that surround Aβ plaques in 5xFAD brains. In in-vitro primary microglial studies, Msn silencing by siRNA decreased Aβ phagocytosis and increased lipopolysaccharide-induced production of the pro-inflammatory cytokine, tumor necrosis factor (TNF). In network analysis of human brain proteomic data, Msn was a hub protein of an inflammatory co-expression module positively associated with AD neuropathological features and cognitive dysfunction. Conclusions: Using FACS coupled with TMT-MS as the method of choice for microglial proteomics, we define a core set of highly-abundant adult microglial proteins. Among these, we validate Msn as highly-abundant in plaque-associated microglia with relevance to human AD.
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MACS can rapidly isolate cells of interest with relatively high purity without dependence on cell sorters.
“One key strength of the MACS is the ability to rapidly isolate cells of interest with relatively high purity without dependence on cell sorters”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [147]
MACS suffers from contamination by acellular debris or unbound cells despite high cellular purity.
“however, despite high cellular purity, MACS suffers from contamination by acellular debris or unbound cells (Table 2) [147].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [147]
FACS-isolated microglia proteome was significantly enriched in canonical microglial proteins and contained much lower levels of non-microglia proteins compared to MACS-enriched microglia.
“A recent study compared the proteomic profiles of MACS-enriched microglia and FACS-isolated microglia from adult mouse brain and found that the FACS-isolated microglia proteome was significantly enriched in canonical microglial proteins (e.g., Ctsd) and contained much lower levels of non-microglia proteins (e.g., Gfap) [153].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [153]
CD11b+/CD45+ brain cells are mainly infiltrating macrophages, so we exclude these macrophages with our sorting strategy.
“As CD11b+/CD45+ brain cells are mainly infiltrating macrophages53, we exclude these macrophages with our sorting strategy.”
From A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase (2025) · cites this paper as [53]
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- [39]Chen MJ, Ramesha S, Weinstock LD, Gao T, Ping L, Xiao H, Dammer EB, Duong DD, Levey AI, Lah JJ, et al. Microglial ERK signaling is a critical regulator of pro-inflammatory immune responses in Alzheimer’s disease. bioRxiv. 2019:798215.
Cited by
Sorted by citations
Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau
Rayaprolu, S., Higginbotham, L., Bagchi, P., Watson, C. M., Zhang, T., Levey, A. I., Rangaraju, S., & Seyfried, N. T. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00840-3 · Cited by 118 · see citing works
Self-citationEngel, A., Wagner, V., Hahn, O., Foltz, A. G., Atkins, M., Beganovic, A., Guldner, I. H., Lu, N., Saksena, A., Fischer, U., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59860-6 · Cited by 18 · see citing works
Tsumagari, K., Sato, Y., Shimozawa, A., Aoyagi, H., Okano, H., & Kuromitsu, J. (2022) · iScience · doi:10.1016/j.isci.2022.104832 · Cited by 15 · see citing works
An interpretable deep learning framework identifies proteomic drivers of Alzheimer’s disease
Panizza, E., & Cerione, R. A. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1379984 · Cited by 11 · see citing works
- Authors
- Rayaprolu, S., Gao, T., Xiao, H., Ramesha, S., Weinstock, L. D., Shah, J., Duong, D. M., Dammer, E. B., Webster, J. A., Lah, J. J., Wood, L. B., Betarbet, R., Levey, A. I., Seyfried, N. T., & Rangaraju, S.
- Affiliations
- Emory University (US)
- Central South University (CN)
- Georgia Institute of Technology (US)
- Corresponding author
- Seyfried, Nicholas T.
- Rangaraju, Srikant
- ORCID
- Venue
- Molecular Neurodegeneration
- Publisher
- openRxiv
- Published
- 2019-10-17
- Volume
- 15
- Issue
- 1
- Pages
- 28-28
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC7206797
- OpenAlex
- W3021043548
- Cited by
- 71
- References
- 76
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 8 · 2023: 14 · 2022: 21 · 2021: 5 · 2020: 3
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association (P50 AG025688, 37102, 11060)
- Georgia Institute of Technology
- Emory University (R01AG061800, RF1AG057471, UL1 TR002378, R01AG053960, P50AG025688, U01AG061357, AG025688, RF1AG057470)
- National Institutes of Health (K08‐NS099474‐1, AG025688, NS099474-1, UL1TR002378)
- Alzheimer's Disease Research Center, Emory University (P50 AG025688, AG025688)
- School of Medicine, Emory University (UL1-TR002378)
- National Institute on Aging (AG 025688, RF1AG057470, R01AG057911, R01AG057739, U01AG061357, RF1AG062181, U01AG046161, F32AG064862, RF1AG057330, RF1AG057471, P50AG025688, R21AG056781, R01AG053960, R01AG061800)
- National Institute of General Medical Sciences (T32GM008433)
- National Institute of Neurological Disorders and Stroke (K08-NS099474-1, K08NS099474, R01NS114130, P30NS055077)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- moesin, microglia, Alzheimer's disease, magnetic cell separation, fluorescence-activated cell sorting, amyloid plaques, amyloid-beta phagocytosis, neuroinflammation, TNF-α, 5xFAD mice, hub proteins, co-expression network
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Endoplasmic Reticulum, Flow Cytometry, Humans, Macrophages, Microfilament Proteins, Microglia, Proteomics, Mice, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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