Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

McGeer, Patrick L.; Itagaki, S.; Boyes, Barry E.; McGeer, Edith G.

doi:10.1212/wnl.38.8.1285

Cited by 2,584 publications

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“…Thus in PD itself, α‐synuclein itself might be an antigen used by MHC II during antigen presentation and thus leading to the observed glial infiltration in PD (Hunot and Hirsch, 2003). However it has been also demonstrated that MHC II is upregulated in Parkinson brains, and was not linked to the presence of Lewy‐bodies, indicating, that α‐synuclein might only play a minor role in the recruitment of MHC II positive microglia, and invasion occurs due to the neuronal injury and the associated phagocytosis (Imamura et al, 2003; McGeer et al, 1988). …”

Section: Discussionmentioning

confidence: 99%

“…Under normal conditions the central nervous system expresses low levels of MHC II (Shrikant and Benveniste, 1996); however increases in MHC II levels have been documented in a number of pathological states including multiple sclerosis (Hofman et al, 1986) and Alzheimer's disease (Parachikova et al, 2007). Increases in MHC II‐positive cells have long been recognised in human post‐mortem tissue from PD patients (Imamura et al, 2003; McGeer et al, 1988). Also an increase in the number of MHC II‐positive microglia is seen in mice treated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a drug which induces a PD‐like disease in mice (Kurkowska‐Jastrzebska et al, 1999a, 1999b).…”

Section: Introductionmentioning

confidence: 99%

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Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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“…Microglia are present throughout the brain and are higher in the substantia nigra (12% of cells) than in the cortex (only 5%) (Kim et al, 2000;Lawson et al, 1990). In PD patients, the substantia nigra was found to have more than 6-time the number of reactive microglia as compared to the control brains (McGeer et al, 1988a;McGeer et al, 1988b). Microglia activation is involved in the cytotoxicity of neurotoxins such as MPTP, rotenone, substance P, and methamphetamine (Block et al, 2006;Delgado, 2003;Gao et al, 2002;Gao et al, 2003b;Scheller et al, 2005;Thomas et al, 2004;Wu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Miller

Sun

2007

Brain Research

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Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP + ), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCδ) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCδ inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCδ-and ERK-dependent pathways.

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“…Resting microglial cells can be activated by Ab in brain, they migrate and surround the region of compact Ab deposits, where they help removing Ab ( [7,65,73,144,155,248]). These data argue in favour of an essential role of microglia cells.…”

Section: Alzheimer's Disease and Neuroinflammationmentioning

confidence: 99%

“…The observation that activated microglia are present at amyloid deposits in human AD and in animal models of this disease suggested that it might play a pathogenic role as a result of their chronic activation, although the presence of cytoplasmic Ab granules in plaque-associated glia and microglia suggest that these cells participate in the clearance of Ab ( [7,42,65,73,125,144,155,180,215,248,254,257,259]). However, this hypothesis is hard to prove using experimental models of this disease in which many pathological features occur, namely amyloid deposition, neurofibrillary tangle formation, inflammation, neuritic and neuronal loss, synaptic and neuronal dysfunction, vascular alterations [197].…”

Section: Animal Models Of Alzheimer's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

271

206

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

Cited by 2,584 publications

References 0 publications

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

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