CoChat
Sign Up
Cited by 128Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 70 of the 71 references it cites were found in a registry or an index.

Phenotypic profile of alternative activation marker CD163 is different in Alzheimer’s and Parkinson’s disease

Open access
Pey, Peixuan, Pearce, Ronald KB, Kalaitzakis, Michail E, Griffin, W Sue T, Gentleman, Steve M·2014·Acta Neuropathologica Communications
DOI 10.1186/2051-5960-2-21PMC PMC3940003
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Microglial activation is a pathological feature common to both Alzheimer's and Parkinson's diseases (AD and PD). The classical activation involves release of pro-inflammatory cytokines and reactive oxygen species. This is necessary for maintenance of tissue homeostasis and host defense, but can cause bystander damage when the activation is sustained and uncontrolled. In recent years the heterogeneous nature of microglial activation states in neurodegenerative diseases has become clear and the focus has shifted to alternative activation states that promote tissue maintenance and repair. We studied the distribution of CD163, a membrane-bound scavenger receptor found on perivascular macrophages. CD163 has an immunoregulatory function, and has been found in the parenchyma in other inflammatory diseases e.g. HIV-encephalitis and multiple sclerosis. In this study, we used immunohistochemistry to compare CD163 immunoreactivity in 31 AD cases, 27 PD cases, and 16 control cases. Associations of microglia with pathological hallmarks of AD and PD were investigated using double immunofluorescence. RESULTS: Parenchymal microglia were found to be immunoreactive for CD163 in all of the AD cases, and to a lesser extent in PD cases. There was prominent staining of CD163 immunoreactive microglia in the frontal and occipital cortices of AD cases, and in the brainstem of PD cases. Many of them were associated with Aß plaques in both diseases, and double staining with CD68 demonstrates their phagocytic capability. Leakage of fibrinogen was observed around compromised blood vessels, raising the possibility these microglia might have originated from the periphery. CONCLUSIONS: Increase in microglia's CD163 immunoreactivity was more significant in AD than PD, and association of CD163 immunoreactive microglia with Aβ plaques indicate microglia's attraction towards extracellular protein pathology, i.e. extracellular aggregates of Aβ as compared to intracellular Lewy Bodies in PD. Double staining with CD163 and CD68 might point towards their natural inclination to phagocytose plaques. Fibrinogen leakage and compromise of the blood brain barrier raise the possibility that these are not resident microglia, but systemic macrophages infiltrating the brain.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/2051-5960-2-21

Cites

70 of 70 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Schematic representation of the structure and domain organization of membrane-bound CD163. CD163 consists of a 1003 amino acid extracellular portion with 9 class B scavenger receptor cysteine-rich (SRCR) domains, with domains 6 and 7 separated by a 31 amino acid linker. This linker is composed of many proline, serine and threonine residues (PST). Another PST linker connects the last SRCR domain to the transmembrane segment, which is made up of 24 amino acids. The intracellular cytoplasmic domain ranges from 49 to 89 amino acids that contain consensus sequences for phosphorylation and internalization.
Figure 1 Schematic representation of the structure and domain organization of membrane-bound CD163. CD163 consists of a 1003 amino acid extracellular portion with 9 class B scavenger receptor cysteine-rich (SRCR) domains, with domains 6 and 7 separated by a 31 amino acid linker. This linker is composed of many proline, serine and threonine residues (PST). Another PST linker connects the last SRCR domain to the transmembrane segment, which is made up of 24 amino acids. The intracellular cytoplasmic domain ranges from 49 to 89 amino acids that contain consensus sequences for phosphorylation and internalization.CC BY · PubMed Central
Figure 2 Immunohistochemical detection of CD163. (a-c) a- PVM immunoreactive for CD163 in the frontal cortex of a control case. b- Parenchymal microglia immunoreactive for CD163 in the occipital cortex of an AD case. c- CD163 immunoreactive microglia in close proximity to meningeal spaces in the occipital lobe of an AD case. (d-f) Range of CD163 immunoreactivity (based on %area) in microglia from d-mild, e-moderate, to f-severe.
Figure 2 Immunohistochemical detection of CD163. (a-c) a- PVM immunoreactive for CD163 in the frontal cortex of a control case. b- Parenchymal microglia immunoreactive for CD163 in the occipital cortex of an AD case. c- CD163 immunoreactive microglia in close proximity to meningeal spaces in the occipital lobe of an AD case. (d-f) Range of CD163 immunoreactivity (based on %area) in microglia from d-mild, e-moderate, to f-severe.CC BY · PubMed Central
Figure 3 Comparison of percentage area of CD163 immunoreactive microglia in various brain regions of AD and PD cases. %area of CD163 immunoreactive microglia was assessed in all available brain regions in 31 AD cases and 27 PD cases. Significant differences were observed from comparison of the median between the frontal lobe and hippocampal regions (CA1, CA3, CA4, subiculum and entorhinal cortex) of AD and PD cases. Columns represent mean %area of CD163 immunoreactive microglia in their respective brain regions for AD and PD cases.
Figure 3 Comparison of percentage area of CD163 immunoreactive microglia in various brain regions of AD and PD cases. %area of CD163 immunoreactive microglia was assessed in all available brain regions in 31 AD cases and 27 PD cases. Significant differences were observed from comparison of the median between the frontal lobe and hippocampal regions (CA1, CA3, CA4, subiculum and entorhinal cortex) of AD and PD cases. Columns represent mean %area of CD163 immunoreactive microglia in their respective brain regions for AD and PD cases.CC BY · PubMed Central
Figure 4 Double immunofluorescence of CD163 with microglia/macrophage markers Iba1 and MRC1. (a and b) Double immunofluorescence for CD163 (red) and Iba1 (green) in the occipital cortex of AD cases. Not all CD163 immunoreactive microglia stained for Iba1 (arrows), a marker highly specific for microglia. This suggests that CD163 immunoreactive parenchyma microglia might originate from systemic cells that have yet to obtain an Iba1 immunoreactive profile. The presence of microglia immunoreactive for both Iba1 and CD163 also indicate that resident microglia might be able to upregulate CD163 with stimulation from the periphery. (c) Double immunofluorescence for CD163 (red) and MRC1 (green) in the occipital cortex of an AD case. CD163 co-stains PVM with MRC1. MRC1 immunoreactivity is limited to PVM (circled). This is in concordance with findings that MRC1 is restricted to PVM despite a clear BBB breakdown.
Figure 4 Double immunofluorescence of CD163 with microglia/macrophage markers Iba1 and MRC1. (a and b) Double immunofluorescence for CD163 (red) and Iba1 (green) in the occipital cortex of AD cases. Not all CD163 immunoreactive microglia stained for Iba1 (arrows), a marker highly specific for microglia. This suggests that CD163 immunoreactive parenchyma microglia might originate from systemic cells that have yet to obtain an Iba1 immunoreactive profile. The presence of microglia immunoreactive for both Iba1 and CD163 also indicate that resident microglia might be able to upregulate CD163 with stimulation from the periphery. (c) Double immunofluorescence for CD163 (red) and MRC1 (green) in the occipital cortex of an AD case. CD163 co-stains PVM with MRC1. MRC1 immunoreactivity is limited to PVM (circled). This is in concordance with findings that MRC1 is restricted to PVM despite a clear BBB breakdown.CC BY · PubMed Central
Figure 5 Double immunofluorescence of CD163 with fibrinogen. (a and b) Immunofluorescence for fibrinogen in the (a) occipital cortex of an AD case and (b) cingulate cortex of a PD case. Fibrinogen was found to exude from compromised blood vessels in both AD and PD cases, but to a lesser extent in the PD cases. Arrows point to compromised blood vessels where fibrinogen has leaked into the surrounding parenchyma. (c and d) Double immunofluorescence for CD163 (red) and fibrinogen (green) in the (c) frontal and (d) occipital cortex of AD cases. Presence of CD163 immunoreactive microglia at close proximity to areas of fibrinogen leakage in the parenchyma. This raises the possibility that CD163 immunoreactive microglia are a result of migration from the periphery. Astrocytes were also found to have fibrinogen immunoreactivity.
Figure 5 Double immunofluorescence of CD163 with fibrinogen. (a and b) Immunofluorescence for fibrinogen in the (a) occipital cortex of an AD case and (b) cingulate cortex of a PD case. Fibrinogen was found to exude from compromised blood vessels in both AD and PD cases, but to a lesser extent in the PD cases. Arrows point to compromised blood vessels where fibrinogen has leaked into the surrounding parenchyma. (c and d) Double immunofluorescence for CD163 (red) and fibrinogen (green) in the (c) frontal and (d) occipital cortex of AD cases. Presence of CD163 immunoreactive microglia at close proximity to areas of fibrinogen leakage in the parenchyma. This raises the possibility that CD163 immunoreactive microglia are a result of migration from the periphery. Astrocytes were also found to have fibrinogen immunoreactivity.CC BY · PubMed Central
Figure 6 Double immunofluorescence detection of CD163 with Aβ, α-syn and CD68. (a) Double immunofluorescence for CD163 (red) and Aβ (green) in the occipital cortex of an AD case. CD163 immunoreactive microglia clusters around dense cored plaques. (b) Double immunofluorescence for CD163 (red) and α-syn (green) in the frontal cortex of a PD case. CD163 immunoreactive microglia cluster around extracellular LBs. Most of the LBs were intracellular and did not coincide with CD163 immunoreactive microglia. It is predictable that these microglia would react with abnormal aggregates of protein found extracellularly, instead of intracellular pathology. (c) Double immunofluorescence for CD163 (red) and tau (green) in the hippocampus of an AD case. CD163 immunoreactive microglia are in close proximity with neuropil thread but with no specific associations. (d) Double immunofluorescence for CD163 (red) and CD68 (green) in the frontal cortex of an AD case. CD68 is a marker for lysosomes; association (arrow) indicates possible phagocytic properties of CD163 immunoreactive microglia, reinforcing its role as a scavenger receptor.
Figure 6 Double immunofluorescence detection of CD163 with Aβ, α-syn and CD68. (a) Double immunofluorescence for CD163 (red) and Aβ (green) in the occipital cortex of an AD case. CD163 immunoreactive microglia clusters around dense cored plaques. (b) Double immunofluorescence for CD163 (red) and α-syn (green) in the frontal cortex of a PD case. CD163 immunoreactive microglia cluster around extracellular LBs. Most of the LBs were intracellular and did not coincide with CD163 immunoreactive microglia. It is predictable that these microglia would react with abnormal aggregates of protein found extracellularly, instead of intracellular pathology. (c) Double immunofluorescence for CD163 (red) and tau (green) in the hippocampus of an AD case. CD163 immunoreactive microglia are in close proximity with neuropil thread but with no specific associations. (d) Double immunofluorescence for CD163 (red) and CD68 (green) in the frontal cortex of an AD case. CD68 is a marker for lysosomes; association (arrow) indicates possible phagocytic properties of CD163 immunoreactive microglia, reinforcing its role as a scavenger receptor.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 71 references

Cited by

Sorted by citations

Items 101–125 of 125

Related

See all

Metadata

Authors
Pey, P., Pearce, R. K., Kalaitzakis, M. E., Griffin, W. S. T., & Gentleman, S. M.
Affiliations
  • Imperial College London (GB)
  • University of Arkansas for Medical Sciences (US)
Corresponding author
  • Pey, Peixuan
  • Gentleman, Steve M
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2014-02-14
Volume
2
Issue
1
Pages
21-21
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/2051-5960-2-21
PMC
PMC3940003
OpenAlex
W2147311470
Cited by
128
References
71
Citations by year
2026: 7 · 2025: 12 · 2024: 10 · 2023: 18 · 2022: 14 · 2021: 11 · 2020: 16 · 2019: 11 · 2018: 8 · 2017: 9 · 2016: 7 · 2015: 5
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Parkinson's UK (G0909, J-1402)
  • Imperial College London
  • National Institutes of Health (AG12411)
  • National Institute on Aging (AG 12411, P01AG012411)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
CD163, Alzheimer's disease, Parkinson's disease, amyloid plaques, Lewy bodies, CD68, blood-brain barrier, perivascular macrophages, phagocytosis, neuroinflammation
MeSH terms
CD68 Molecule, CD163 Antigen, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Calcium-Binding Proteins, Cell Count, DNA-Binding Proteins, Female, Fibrinogen, Humans, Macrophages, Male, Membrane Glycoproteins, Microfilament Proteins, Middle Aged, Neurologic Examination, Parkinson Disease, Receptors, Cell Surface, Receptors, Immunologic, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Amyloid beta-Peptides, Microglia, Plaque, Amyloid

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review