In various regions of the brain in PD

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Parkinson Diseases Manual By Lianna Marie

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The presence of activated microglia and the absence of reactive astrocytosis in the sub-stantia nigra of patients with PD suggest microglial involvement in the pathological process of dopamine neurons (McGeer et al., 1988; McGeer and McGeer, 1995; Mirza et al., 2000). We (Imamura et al., 2003) showed MHC class II (CR3/43)-positive activated microglia to be widely distributed not only in the substantia nigra and putamen, but also in various brain regions of PD patients, frequently in association with alpha-synuclein-positive Lewy neurites and monoaminergic neurons. In normal brains, many Ki-M1p-positive resting microglia, but only few MHC class II (CR3/43)-positive activated microglia were seen in the substantia nigra and putamen. In PD brains, however, MHC class II (CR3/43)-positive ramified microglia were seen in those regions. PD patients were shown to have a significantly higher number of MHC class II (CR3/43)-positive microglia compared with normal controls. The cell count of MHC class II (CR3/43)-positive micro-glia in PD increased as the neurodegeneration of pigmented cells in the substantia nigra advanced. Moreover, a significantly higher number of MHC class II (CR3/43)-positive microglia were also observed in the hippocampus (HC), transentorhinal cortex (TC), cingulate cortex (CC) and temporal cortex (TC) in PD compared with normal controls. In the early stages in PD, MHC class II (CR3/43)-positive microglia in the putamen were associated with intensively tyrosine hydroxylase (TH)-positive dop-amine neurites without degeneration. In the advanced stage in PD, MHC class II (CR3/43)-positive microglia in the sub-stantia nigra were associated with damaged TH-positive dopamine neurons and neurites. MHC class II (CR3 /43)-positive microglia were also associated with non-degenerated serotonin (WH-3)-positive nerve terminals without degeneration in the substantia nigra. In the cingulate cortex in PD, activated microglia were frequently associated with alpha-synuclein-positive Lewy neurites. These immunohistochemical observations on PD brains suggest that activated microglia may act for either neuroprotection or neurotoxicity depending upon the brain regions and the stage of disease. We speculate that there may be neuroprotective and neurotoxic subtypes of microglia producing different kinds and different amounts of cytokines, neurotrophins, reactive oxygen species (ROS), and reactive nitrogen species (RNS), and that activated microglia in the nigro-striatal region in PD may be non-toxic subtype acting for neuroprotection at least in the early stage but may change to neurotoxic subtype causing neurodegeneration during the progression of the disease.

Our immunohistochemical results suggesting the neuroprotective or neurotoxic dual roles of activated microglia associated with healthy or damaged neurons and neu-rites in various brain regions in PD are schematically summarized in Fig. 1.

Substantia Nigra

Fig. 1. Schematic diagram showing the dual potential roles of microglia in PD. In parkinsonian brains, activated microglia are observed not only in the substantia nigra (SN) and caudate-putamen (C-P) but also in other brain regions such as pallidum and cingulate cortex. Activated microglia associated with neurons or neurites without degeneration may be non-toxic and act for neuroprotection, whereas activated microglia associated with degenerated neurons and neurites may be neurotoxic and promote neurodegeneration. TE transenthorhinal cortex; CC

cingulate cortex; TC temporal cortex; HC hippocampus

Fig. 1. Schematic diagram showing the dual potential roles of microglia in PD. In parkinsonian brains, activated microglia are observed not only in the substantia nigra (SN) and caudate-putamen (C-P) but also in other brain regions such as pallidum and cingulate cortex. Activated microglia associated with neurons or neurites without degeneration may be non-toxic and act for neuroprotection, whereas activated microglia associated with degenerated neurons and neurites may be neurotoxic and promote neurodegeneration. TE transenthorhinal cortex; CC

cingulate cortex; TC temporal cortex; HC hippocampus

Expression of cytokines in the hippocampus and putamen in PD is different from that in LBD

Activated microglia have multiple roles. First, MHC II-positive activated microglia act for antigen presentation. Second, activated microglia phagocytose damaged cells. Third, activated microglia produce neurotoxic substances such as pro-inflammatory cytokines that are pleiotropic and either neurotoxic or neuroprotective like TNF-alpha, IL-lbeta and IL-6, superoxide anions (ROS), nitric oxide (RNS), and glutamate. Fourth, activated microglia also produce neurotro phic substances such neurotrophins as BDNF, IL-6 and TNF-alpha that can also act for neuroprotection. As described above, we (Imamura et al., 2003) observed activated microglia in PD brain not only in the nigro-striatum but also in the hippocampus. We (Imamura et al., 2003, 2005) also observed in LBD activated microglia in the nigro-stria-tum and hippocampus. Neuronal degeneration in the putamen was observed in both PD and LBD, whereas neuronal loss in the hippocampus was observed in LBD, but not in PD without dementia. In order to examine whether activated microglia in the putamen and hippocampus in PD and LBD are neuro-

toxic or neuroprotective, we (Imamura et al., 2005) compared the expression of cytokines and neurotrophins in the hippocampus and putamen in postmortem brains in PD, LBD/ DLB, and normal controls.

In normal controls, neuronal loss and activated microglia were not observed in the hippocampus CA 2/3 region, and neurons were strongly BDNF-positive. Immunohisto-chemical examination of the hippocampus CA 2/3 region in PD showed that the number of MHC II (R3/43)-positive microglia increased, which were also ICAM-1 (CD54)-, LFA-1 (CD11a)-, TNF-alpha-, and IL-6-posi-tive. Alpha-synuclein-positive cells were also observed. BDNF-positive neurons were only slightly decreased in PD as compared with normal controls. In the hippocampus in LBD, the number of MHC-II (CR3/43)-positive microglia and alpha-synuclein-positive cells increased more than those in PD. Furthermore, in LBD all neurons were very weakly stained by anti-BDNF. These immunohisto-chemical data on the hippocampus CA 2/3 indicate that activated microglia increase both in PD and LBD, but that the content of neurotrophic BDNF drastically decreases specifically in LBD.

Expression of mRNAs of cytokines and neurotrophins was examined by RT-PCR in the hippocampus and putamen in normal controls, PD, and LBD. In the hippocampus, mRNA levels of IL-6 and TNF-alpha increased in both PD and LBD, but mRNA levels of BDNF greatly decreased in LBD, as compared with those of normal controls and PD. In the putamen, mRNA levels of IL-6 increased in both PD and LBD. In contrast, mRNA levels of BDNF increased in PD, but decreased in LBD. We (Mogi and Nagatsu, 2002) previously reported by ELISA that the content of BDNF protein decreased in the striatum in PD. Therefore, increased level of BDNF mRNA in PD is speculated to be a compensatory change probably by activated microglia. These different changes in mRNA levels of IL-6 and

BDNF in PD and LBD suggest that activated microglia in the hippocampus and putamen in PD and LBD may be different in properties and may secrete different kinds and different amounts of cytokines and neurotro-phins such as IL-6 and BDNF. We speculate that activated microglia in the hippocampus may be neuroprotective in PD and neurol-toxic in LBD (Imamura et al., 2005).

Two subsets of microglia and two clones of microglia with neurotoxic and neuroprotective properties are isolated in terms of intracellular ROS production induced by phorbol myristate acetate (PMA) stimulation

We separated two subsets of microglia from mouse brain by cell sorting based on profiles of intracellular ROS production induced by PMA. One subset of microglia produced greater amounts of ROS than another subset of microglia. The results suggest that there are at least two subsets of microglia in mouse brain; one active subset and another inactive subset in production of ROS upon stimulation by PMA. In supporting this hypothesis, two cell lines of microglia, Ra2 cells and 6-3 cells, were generated by spontaneous immortalization of primary mouse microglia. Both clones were dependent on granulocyte macrophage colony-stimulating factor (GM-CSF). The GM-CSF-dependent Ra2 microglia did not produce ROS by PMA stimulation. In contrast, the GM-CSF-dependent 6-3 microglia showed increasing ROS production upon stimulation by PMA. N18 neuronal cells were sensitive to oxidative stress by hydrogen peroxide, and showed dose-dependent apoptotic cell death by the addition of hydrogen peroxide. N18 cells cultured in the presence of 50 mM hydrogen peroxide died almost completely by apoptosis. When the N18 neuronal cells were co-cultured with macrophage RAW264.7 cells or 6-3 microglia cells and stimulated with PMA, cell viability of the neuronal cells decreased as determined by cell viability assay (WST assay, PI dye exclusion assay, and TUNEL staining). On the contrary cell viability of the neuronal N18 cells increased by co-culture with Ra2 microglia. These results show 6-3 microglia to be neurotoxic and Ra2 microglia to be neuro-protective when these cells are co-cultured with neuronal cells, supporting our concept that there may exist neurotoxic and neuropro-tective subsets of microglia in the brain.

In agreement with our hypothesis, Hirsch et al. (1998) also proposed separate populations of microglia; one subpopulation of glial cells may play a neuroprotecrive role by metabolizing dopamine and scavenging oxygen free radicals and another that may be deleterious to dopamine neurons by producing NO and toxic proinflammatory cytokins.

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