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Cited by 562Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesInflammasome and immune disorders

Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains

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Walker, Douglas G., Lue, Lih-Fen·2015·Alzheimer's Research & Therapy
DOI 10.1186/s13195-015-0139-9PMC PMC4543480
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Abstract

Inflammatory responses in the brain, which can be demonstrated by changes in properties of microglia, the brain-resident macrophages, are a common feature of human neurodegenerative diseases. Different monocyte/macrophage phenotypes have been defined by changes in expression of cytokines, receptors and other markers as a response to different classes of stimuli. Monocytes, macrophages and microglia can have a range of phenotypes with associated properties depending on their microenvironment. Macrophage/microglia polarization states have been defined as classical activation (M1), alternative activation (M2a), type II alternative activation (M2b) or acquired deactivation (M2c). Available markers for identifying microglial phenotypes in human brains are still limited; those available provide incomplete information on the functions or polarization states of microglia observed in tissues from diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. The most widely used marker to describe activated microglia in human brains, particularly diseased brains, has been HLA-DR, the major histocompatibility complex II protein. HLA-DR-positive microglia can have a wide range of activation morphologies that are affected not only by disease pathology, but also by their differentiation states and brain regions. Two other widely used markers to identify microglia in human brains are ionized calcium binding adaptor molecule-1 and CD68. Although their expression changes in diseased brains, these markers do not show specificity for different phenotypes. Over the years there have been studies with additional markers that attempt to further define microglial properties, particularly in Alzheimer’s disease brains. Most studies have employed immunohistochemical techniques to identify microglia in tissue sections, but recent advances in this field have allowed gene expression profiling of microglia upon immediate isolation from brains. We will review which markers might better define different activation phenotypes of microglia in human brains and whether they fit into current microglial polarization schemes.

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  • Associating single markers to a distinct microglial phenotype is difficult, since most markers are expressed in several or even all microglial functional states.

    “However, as we will describe in this review, associating single markers to a distinct phenotype is difficult, since most markers are expressed in several or even all microglial functional states (Figure 1, [2]).”

    From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [2]

    The Abstract says that widely used microglial markers do not distinguish different phenotypes, and the CD68 section says that both M1- and M2-polarized cells can express CD68. These passages support the difficulty of assigning a phenotype from a single marker, but do not establish that most markers are expressed in several or all functional states. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Ten studies identified increases in Iba1 cell counts, staining intensity or expression in Alzheimer's disease compared with control samples in at least one brain region.

    “Ten studies identified increases in Iba1 cell counts, staining intensity or expression in AD compared with control samples in at least one brain region,20, 60, 61, 62, 63, 64, 65, 66, 67, 68”

    From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [60]

    The “Microglia in human brains” section says IBA-1 expression can increase in activated microglia, but it does not report an increase in IBA-1 cell counts, staining, or expression in Alzheimer’s disease samples compared with non-AD controls. Its reported case comparison concerns immunized and control AD cases and found no overall difference in IBA-1 reactivity; the section has no page number in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Approximately twice the volume of Aβ is engulfed within CD68 in 5xFAD microglia compared with 5xFAD SykΔMG microglia.

    “Similarly, approximately twice the volume of Aβ was engulfed within CD68, a well-described marker of microglial phagolysosomes (Walker and Lue, 2015), in 5xFAD microglia compared with 5xFAD SykΔMG microglia (Figures 5C and 5D).”

    From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Walker and Lue, 2015

  • IBA1 cannot be used to distinguish between functional microglial phenotypes.

    “Even though IBA1 is often characterized as a typical microglial activation marker [8,9,10], it cannot be used to distinguish between functional microglial phenotypes [2].”

    From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [2]

  • CD68 is indicative of phagocytic activity and is upregulated in cell culture after treatment with pro-inflammatory cytokines, lipopolysaccharide and IFNγ.

    “It is indicative of phagocytic activity [2], and is upregulated in cell culture experiments after treatment with pro-inflammatory cytokines, lipopolysaccharide (LPS) and IFNγ [98].”

    From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [2]

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Cited by

Sorted by citations

Authors
Walker, D. G., & Lue, L.-F.
Affiliations
Banner Sun Health Research Institute (US)
Corresponding author
Walker, Douglas G.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2015-08-19
Volume
7
Issue
1
Pages
56-56
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-015-0139-9
PMC
PMC4543480
OpenAlex
W1667616536
Cited by
562
References
10
Citations by year
2026: 25 · 2025: 51 · 2024: 63 · 2023: 73 · 2022: 81 · 2021: 79 · 2020: 44 · 2019: 39 · 2018: 45 · 2017: 43 · 2016: 19
FWCI
19.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (U24 NS072026, 05-901, 211002)
  • Alzheimer's Association
  • Sun Health Foundation (211002, 05-901, U24 NS072026)
  • Arizona Department of Health Services (U24 NS072026, 05-901, 211002, Contract 211002)
  • Arizona Biomedical Research Commission (05–901, Contracts 4001, 0011, 05‐901 and 1001, U24 NS072026, 4001, 0011, 05-901, and 1001, 211002)
  • National Institutes of Health (U24NS07-2026, 05-901, 211002, R21AG044068-1)
  • National Institute on Aging (R21AG034409, R21AG034409-A1, R21AG044068-1, R21AG044068)
  • National Institute of Neurological Disorders and Stroke (NS072026, 211002, U24NS072026, 05-901)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
microglia, microglial polarization, neurodegenerative diseases, HLA-DR, Iba1, CD68, microglial markers, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuroinflammation
MeSH terms
Brain, Humans, Macrophages, Phenotype, Biomarkers, Microglia, Neurodegenerative Diseases

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