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

Peixuan Pey, Ronald K B Pearce, Michail E Kalaitzakis, W Sue T Griffin, Steve M Gentleman, Peixuan Pey, Ronald K B Pearce, Michail E Kalaitzakis, W Sue T Griffin, Steve M Gentleman

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.

Figures

Figure 1
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 2
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 3
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 4
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 5
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 6
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.

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