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. 2017 Sep;369(3):445-454.
doi: 10.1007/s00441-017-2626-8. Epub 2017 May 2.

Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson's and Alzheimer's disease

Sandra Gellhaar  1 , Dan Sunnemark  2   3 , Håkan Eriksson  2 , Lars Olson  1 , Dagmar Galter  4
Affiliations

Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson's and Alzheimer's disease

Sandra Gellhaar et al. Cell Tissue Res. 2017 Sep.

Abstract

Myeloperoxidase (MPO) is a key enzyme in inflammatory and degenerative processes, although conflicting reports have been presented concerning its expression in the brain. We studied the cellular localization of MPO and compared numbers of MPO cells in various brain regions between neurologically healthy individuals and patients with Parkinson's disease (PD) or Alzheimer's disease (AD; n = 10-25). We also investigated two rodent PD models. MPO immunoreactivity (ir) was detected in monocytes, perivascular macrophages and amoeboid microglia in the human brain parenchyma, whereas no co-localization with glial fibrillary acidic protein (GFAP) ir was observed. In the midbrain, caudate and putamen, we found a significant increase of MPO-immunoreactive cells in PD compared with control brains, whereas in the cerebellum, no difference was apparent. MPO ir was detected neither in neurons nor in occasional small beta-amyloid-immunoreactive plaques in PD or control cases. In the frontal cortex of AD patients, we found significantly more MPO-immunoreactive cells compared with control cases, together with intense MPO ir in extracellular plaques. In the hippocampus of several AD cases, MPO-like ir was observed in some pyramidal neurons. Neither rapid dopamine depletion in the rat PD model, nor slow degeneration of dopamine neurons in MitoPark mice induced the expression of MPO ir in any brain region. MPO mRNA was not detectable with radioactive in situ hybridization in any human or rodent brain area, although myeloid cells from bone marrow displayed clear MPO signals. Our results indicate significant increases of MPO-immunoreactive cells in brain regions affected by neurodegeneration in PD and AD, supporting investigations of MPO inhibitors in novel treatment strategies.

Keywords: Frontal cortex; Hippocampus; In situ hybridization; Neuroinflammation; Substantia nigra.

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Conflict of interest statement

Disclosure of potential conflicts of interest

D.S and H.E were full-time employees of AstraZeneca at the time of the study. L.O. and D.G. have received grants from AstraZeneca. L.O. is co-owner of a company that has commercial rights to MitoPark mice. S.G. declares no conflict of interest.

Research involving human post-mortem tissue and animals

The regional ethics committee in Stockholm has approved all studies on post-mortem human tissue. All applicable international and national guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution and have been approved by the regional animal ethics committee in Stockholm.

Figures

Fig. 1
Fig. 1
Typical cellular localization of myeloperoxidase (MPO) expression in human and rodent brain tissues. In all brain areas, analyzed cells with MPO immunoreactivity (ir) were often located in small blood vessels (a) or in the brain parenchyma close to blood vessels (b) and, in some cases, in the wall of larger blood vessels (c). In brain tissue from AD patients, MPO ir was also detected in amyloid plaques and round cells with MPO ir were occasionally found close to the extracellular protein aggregates (d). Adjacent brain sections were stained for histocompatibility antigen (HLA-DR; e) and glial fibrillary acidic protein (GFAP; f) to reveal the shape and size of ramified microglia and astrocytes, respectively. Examples of MPO-immunoreactive cells are taken from the hippocampus of a control case (a, c), the caudate nucleus of a case with Parkinson’s disease (PD; b) and the hippocampus of a case with Alzheimer’s disease (AD; d). The sections showing HLA and GFAP staining were taken adjacent to sections from the caudate nucleus of the PD case in b. In rat brains, cells with MPO ir were only detected at the site of toxin injection 24 h after operation, both in fresh frozen rat brain tissue (g) and in brain tissue from perfusion-fixed rats (h). In fresh frozen tissue, MPO-positive cells were often surrounded by a halo of ir, whereas in tissue from animals perfused with fixative solution, the ir was restricted to cell boundaries. In rat bone marrow smears, MPO mRNA was readily detected by radioactive in situ hybridization (i). Bar 25 μm
Fig. 2
Fig. 2
Increased MPO expression in PD restricted to brain areas affected by neuropathology. Numbers of MPO-immunoreactive cells are significantly higher in the putamen and caudate nucleus from PD patients compared with controls (P < 0.001, t = 4.66, df = 18; P = 0.001, t = 3.72, df = 18, respectively, in a). Examples of MPO-immunoreactive cells are shown in the putamen of a PD case (b). The number of MPO-immunoreactive cells was significantly higher in the substantia nigra of PD patients compared with controls (P < 0.001, t = 5.10, df = 32, in c). Examples of MPO-immunoreactive cells are shown in the midbrain of PD patients, close to the remaining neuromelanin-containing dopamine neurons (d). The number of MPO-immunoreactive cells in the cerebellar cortex of PD patients did not differ from that of control cases (P > 0.05, in e). Examples of MPO-immunoreactive cells are shown in the cerebellar cortex of a PD patient (f). Bar 25 μm. **P < 0.01, ***P < 0.005
Fig. 3
Fig. 3
Increased MPO expression in frontal cortex samples from AD patients. The number of MPO-immunoreactive cells was significantly higher in the frontal cortex of AD patients compared with controls (P = 0.003, t = 3.17, df = 63, in a). Examples of MPO-immunoreactive cells are shown in the frontal cortex of a control case (b) and an AD patient (c). Many extracellular protein aggregates show immunostaining for amyloid beta (APP, d) and also for MPO (e) in samples from AD patients. Bars 25 μm (b, c; d, e). ***P < 0.005
Fig. 4
Fig. 4
MPO expression in hippocampus from AD patients and control cases. Examples of MPO-immunoreactive cells in the CA1 region (a), dentate gyrus (b) and entorhinal cortex (c) of a control case and in the CA1 region (d), dentate gyrus (e) and entorhinal cortex (f) of an AD patient. Some “ghost tangles” are shown scattered between MPO-immunoreactive amyloid plaques in the CA1 region of an AD case (g). Similar cells on the adjacent section are ir for tau (p-TAU; h). A negative control for the staining protocol is shown in i. Bar 25 μm
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