zed: 1) Rodent Parkinson's disease (PD)model: PD,a chronic progressive neurodegenerative disorder, may stem from interactions among aging, genetic susceptibility, and environmental exposure. The identification of multiple causative genes for familial PD indicates important genetic influence in this disease. Unlike other PD-causative genes, -synuclein (-syn) is tightly linked to both familial and sporadic PD. However, how -syn promotes neurodegeneration and affects chronic PD progression remains elusive. Here, we demonstrate that a low-grade and prolonged neuroinflammatory process, triggered by an intraperitoneal injection of an inflammogen lipopolysaccharide (LPS, 1 mg/kg), initiated chronic progressive degeneration of nigral-striatal dopamine neurons and fibers (the signature lesion of PD) in human A53T mutant -syn transgenic mice. Accumulation of insoluble aggregated -syn in nigral neurons as cytoplasmic inclusions that mimic the pathological hallmark of PD, Lewy body was observed in this LPS-treated Tg mice. In contrast, no neurodegeneration, -syn pathology, or chronic neuroinflammation was found in wildtype mice injected with LPS or -syn Tg mice injected with NS, despite the fact that initially LPS produced the same acute systemic and brain inflammatory reactions in both transgenic mice and wildtype mice. Mechanistic studies showing persistent activation of microglia-free radical generating enzymes, iNOS and PHOX also provided a potential link between neuroinflammation and aggregation of -syn. This study provides direct in vivo experimental evidence indicating synergistic effects of genetic predisposition and experimental exposure in the development of PD. Moreover, our two-hit (neuroinflammation and mutant -syn overexpression) animal model reproduces key features of PD. More importantly, the chronic progressive nature, which is absent in most available PD animal models, makes this model invaluable for studying mechanisms of PD progression and screening disease-modifying therapeutics for PD. 2) Mechanism of reactive microgliosis: For the last year, our research focused on the reactive microgliosis is crucial for the maintenance of long-term microglial activation. After demonstrating that continuing neuronal death/damage is crucial for the maintenance of microglial activation, we tried to further understand the molecular mechanisms by studying the role of reactive microgliosis in the creation of the self-propelling cycle. Reactive microgliosis occurs when neurons are damaged and has been generally considered to serve a passive role in cleaning the dead or damaged neurons or debris by phagocytosis. Our recent studies provided convincing evidence indicating that reactive microgliosis play a critical and active role in the formation of a self-propelling cycle and the subsequent neuro-degeneration. We have shown that a spectrum of noxious endogenous compounds in extracellular milieu, generated following neuronal injury, can activate microglia leading to reactive microgliosis. These compounds include membrane breakdown products, abnormally processed, modified or aggregated proteins (e.g.a-synuclein and -amyloid), and leaked cytosolic compounds (e.g.a-synuclein and neuromelanin). It appears that the microglial response to these endogenous toxic signals resembles their response to invading microbes.

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Dang, Duy-Khanh; Shin, Eun-Joo; Kim, Dae-Joong et al. (2018) Ginsenoside Re protects methamphetamine-induced dopaminergic neurotoxicity in mice via upregulation of dynorphin-mediated ?-opioid receptor and downregulation of substance P-mediated neurokinin 1 receptor. J Neuroinflammation 15:52
Zhang, Wei; Gao, Jun-Hua; Yan, Zhao-Fen et al. (2018) Minimally Toxic Dose of Lipopolysaccharide and ?-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation. Mol Neurobiol 55:619-632
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Lu, Ru-Band; Lee, Sheng-Yu; Wang, Tzu-Yun et al. (2017) Long-term heroin use was associated with the downregulation of systemic platelets, BDNF, and TGF-?1, and it contributed to the disruption of executive function in Taiwanese Han Chinese. Drug Alcohol Depend 179:139-145

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