The toxic change of reactive microglia suggests two step activation of microglia in PD

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Based on these in vitro results suggesting the presence of neuroprotective or neurotoxic subsets of activated microglia, we propose a hypothesis of two-step activation of micro-glia in the brain in PD in vivo, as schematically shown in Fig. 2. Ramified resting microglia in the normal brain support neurons for control of neuronal activity, development, and homeostasis in the brain. The observation on activated microglia associated with intensely tyrosine hydroxylase (TH)-positive neurites in the striatum in the early stage of PD and with other non-degenerated neurons and neurites in various brain regions suggest that microglia activated by the first stimuli may act for neuroprotection by producing neurotrophins, neurotrophic cyto-kines, and antioxidant at the first step. The activated microglia at this first step may be neuroprotective. As described above, Sawada with coworkers found that microglia in a cell culture experiment are converted from the neuroprotective to neurotoxic forms upon expression of the HIV-1 Nef protein (Vilhardt et al., 2002). Similar toxic change of activated microglia may occur in PD brain as the second step by other factors such as in

Microglia Isolation

Fig. 2. Schematic diagram showing a hypothesis of two-step activation of microglia. We isolated neuroprotective and neurotoxic subsets of microglia, and also neuroprotective and neurotoxic clones from mouse brain. In addition, Sawada and coworkers (Vilhardt et al., 2002) found in a cell culture experiment that a neuroprotective microglial clone converted from the protective to toxic cells upon transduction of the HIV-1 Nef protein with activation of NADPH oxidase. Based on these results, we propose a hypothesis of two step activation of microglia. Activated microglia by the first stimuli may initially act for neuroprotection by producing protective neurotrophins, cytokines, and antioxidants, but by the second stimuli and unknown regulators may change to be neurotoxic by producing ROS and MPO. This toxic change of activated microglia may promote the progress of PD

Fig. 2. Schematic diagram showing a hypothesis of two-step activation of microglia. We isolated neuroprotective and neurotoxic subsets of microglia, and also neuroprotective and neurotoxic clones from mouse brain. In addition, Sawada and coworkers (Vilhardt et al., 2002) found in a cell culture experiment that a neuroprotective microglial clone converted from the protective to toxic cells upon transduction of the HIV-1 Nef protein with activation of NADPH oxidase. Based on these results, we propose a hypothesis of two step activation of microglia. Activated microglia by the first stimuli may initially act for neuroprotection by producing protective neurotrophins, cytokines, and antioxidants, but by the second stimuli and unknown regulators may change to be neurotoxic by producing ROS and MPO. This toxic change of activated microglia may promote the progress of PD

vasion of serum, viruses, toxic matters, or inflammatory cells in a part of neuroprotective microglia in a specific brain regions such as the nigro-striatum in PD. As the results of toxic change of activated microglia, large amounts of cytotoxic factors such as ROS and RNS produced by NADPH oxidase or MPO may promote neuronal loss.

Conclusion and future prospects

Oxidative stress is thought to play a key role in sporadic PD (Youdim and Riederer, 1997).

Presence of neuroinflammation and oxidative stress may have a causative link in PD. Oxidative stress may trigger microglia activation and neuroinflammation (Hald and Lutharius, 2005).

In the brain from patients with PD, activated microglia are observed not only in the nigro-striatum where cell loss of dopamine neurons occurs, but also in various brain regions such as the hippocampus. The activation of microglia may occur in tow steps. At the first step, the activated microglia produced by unknown stimuli may act for neuro-

protection at least in the early stages of PD. At the second stage by other unknown factors, neuroprotective microglia may be subjected to toxic change that convert microglia from neuroprotective to neurotoxic type to promote the progression of neurodegeneration.

There remain several points to confirm this hypothesis on the role of activated microglia and cytokines in PD. First, the presence of neuroprotective and neurotoxic microglia in the human brain should be confirmed. Second, in vivo evidences of toxic change of microglia are required in some experimental models of PD. Third, the stimuli to activate microglia at the first stage must be identified. Since the causative factors of sporadic PD are speculated to be multiple, the stimuli may also be multiple. Fourth, the factors and unknown regulators for the toxic change of activated microglia must be identified.

The present hypothesis is expected to be useful for developing drugs against PD. Anti-inflammatory drugs have been considered for the treatment of PD. However, such anti-inflammatory drugs should inhibit the toxic change of microglia or act only to toxic subtype of microglia.

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