BCG Vaccine-Induced Neuroprotection in a Mouse Model of Parkinson's Disease
Jing YongGoran LaćanHoa DangTerry HsiehBlake MiddletonClive WasserfallJide TianWilliam P. MelegaDaniel L. Kaufman
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Abstract:
There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions.Keywords:
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The activation of microglia and the various substances they produce have been linked to the pathologic development of Parkinson's disease (PD), but the precise role of microglia in PD remains to be defined. The survival of microglia depends on colony-stimulating factor 1 receptor (CSF1R) signaling, and CSF1R inhibition results in rapid elimination of microglia in the central nervous system. Using a mouse PD model induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treatment, we showed that the depletion of microglia via the CSF1R inhibitor PLX3397 exacerbated the impairment of locomotor activities and the loss of dopaminergic neurons. Further, depletion of microglia augmented the production of inflammatory mediators and infiltration of leukocytes in the brain after MPTP exposure. Microglia depletion-induced aggravation of MPTP neurotoxicity was also seen in lymphocyte-deficient mice. In addition, the depletion of microglia did not affect the production of brain-derived neurotrophic factor, but it dramatically augmented the production of inflammatory mediators by astrocytes after MPTP treatment. Our findings suggest microglia play a protective role against MPTP-induced neuroinflammation and dopaminergic neurotoxicity.—Yang, X., Ren, H., Wood, K., Li, M., Qiu, S., Shi, F.-D., Ma, C., Liu, Q. Depletion of microglia augments the dopaminergic neurotoxicity of MPTP. FASEB J. 32, 3336–3345 (2018). www.fasebj.org
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Previously, we and others have shown an alteration in the expression of the antiapoptotic factor and antioxidant, Bcl-2, and its homolog the proapoptotic factor, Bax, in substantia nigra tissue from C57 black mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This has led to the suggestion that changes in expression of these genes may reflect an attempt by substantia nigra dopaminergic neurons to control oxidative stress induced by inhibition of complex 1 in the mitochondrial electron transport chain. Expression of apoptosis-related genes may help determine whether a neuron survives or dies after injury. Since previous studies in this lab have shown that the monosialoganglioside GM1 can rescue damaged dopamine neurons and promote survival, the present study was conducted to examine the extent to which GM1 can regulate altered Bcl-2 and Bax gene expression in animals challenged with MPTP. Exposure to MPTP (single s.c. injection at 30 mg/kg) caused altered expression of Bcl-2 and Bax mRNA and protein, in the ventral mesencephalic region as demonstrated by RT-PCR and immunohistochemistry. Maximal up-regulation of Bcl-2 and Bax mRNA occurred at 12 h postinjection with a return to normal levels within 24 h for Bcl-2. Bax expression remained elevated at 24 h after MPTP administration. Immunohistochemical labeling in the substantia nigra also showed elevated levels of expression for Bcl-2 and Bax protein, concomitant to the increased mRNA levels, while tyrosine hydroxylase immunohistochemical staining in MPTP-treated animals remained unchanged from that seen in normal animals. The coadministration of MPTP (single s.c. injection at 30 mg/kg) and GM1 (single i.p. injection at 30 mg/kg, 5 min post-MPTP) prevented the previously described increase in both Bcl-2 and Bax mRNA expression in the ventral mesencephalon. In GM1-treated animals both Bcl-2 and Bax mRNA showed a steady-state expression at all time points examined. Similarly, the expression levels of both Bcl-2 and Bax proteins remained unchanged in GM1-treated animals, as did staining for tyrosine hydroxylase. These results suggest that GM1 has the potential to alter the natural course of the neuronal degeneration in Parkinson's disease by influencing gene expression that might be involved in the progressive loss of dopaminergic neurons.
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The dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) replicates many of the pathological hallmarks of Parkinson's disease (PD) in mice via selective destruction of dopamine neurons of the substantia nigra and striatum. Although MPTP has been widely used to study downstream effects following the degeneration of dopaminergic neurons, the underlying mechanisms of MPTP action remain poorly understood. To determine the underlying mechanisms of MPTP action at the protein level, a 2-DE-based proteomics approach was used to evaluate the changes in protein expression in substantia nigra and striatal tissue in C57BL/6 mice after MPTP administration. We identified nine proteins that were markedly altered and are likely to be involved in mitochondrial function, heat shock protein activity, and which contribute enzyme activities for energy metabolism and protein degradation.
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Objective
To study the neuroprotective role of TFP5 in a MPTP-induced mouse model of Parkinson's disease (PD).
Methods
C57BL/6 mice were used as experimental animals. Briefly, 5 consecutive days of intraperitoneal injection of 25 mg/Kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) was applied to induce mouse PD model. The mice were randomized into 5 groups including control group, model group, scrambled TFP5 peptide (Scb) group, TFP5 group and roscovitine group. On the 7th day after the first injection of MPTP, behavior tests were performed, and then western blot method was employed to detect the expression of p25 and phosphorylated MEF2D in substantia nigra.Tyrosine hydroxylase (TH) immunohistochemical staining was performed to observe the apoptosis of dopaminergic neurons in substantia nigra pars compacta (SNpc) 28 days after the first injection of MPTP.
Results
MPTP increased the expression of p25 (0.48±0.10 vs 0.26±0.02, P<0.05) and phosphorylated MEF2D (0.81±0.10 vs 0.22±0.02, P<0.05) in substantia nigra, but decreased the number of dopaminergic neurons in SNpc (348.67±24.40 vs 463.29±19.61, P<0.05), resulting in motor impairment in the model mice (P<0.05). Intraperitoneal injection of 30mg/Kg of TFP5 for 3 days effectively reduced the excessive phosphorylation of MEF2D (0.25±0.12 vs 0.81±0.10, P<0.05) in substantia nigra, rescued dopaminergic neuron reduction of SNpc (422.92±8.41 vs 348.67±24.40, P<0.05), and improved the motor ability of the model mice (P<0.05). Roscovitine exerted almost same neuroprotective role as TFP5, while Scb had no protective effect.
Conclusion
TFP5 can rescue MPTP-induced damage of dopaminergic neurons in substantia nigra, and thus improve motor impairment of model mice, which may be mediated by the inhibition of Cdk5/p25 activity.
Key words:
Parkinson's disease; Cyclin-dependent kinase 5; TFP5; Dopaminergic neurons
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We evaluated the T1 values of the whole and subregions of the substantia nigra (SN) in patients with Parkinson's disease (PD) to identify an imaging biomarker for the early diagnosis of PD. T1 values of the SN of patients with PD were significantly shorter than those of healthy controls and tended to be longer in the lateral part for both groups. T1 values may reflect the pathology of the SN and help assess the degeneration of the SN caused by PD.
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Increasing evidence suggests a pivotal role for neuroinflammation in the pathogenesis of Parkinson disease, but whether activated microglia participate in disease progression remains unclear. To clarify this issue, we determined the numbers of activated microglial cells in the substantia nigra pars compacta and ventral tegmental area of monkeys subacutely and chronically exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys in the subacute MPTP treatment group were killed 1 week after the last MPTP injection; chronically treated monkeys were killed either 6 or 35 months after the last MPTP injection. Subacute MPTP administration induced loss of dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area and microglial activation in the same areas. Chronic MPTP treatment resulted in greater dopaminergic neuron depletion in both treatment groups. Both groups of chronic MPTP-treated monkeys showed increased numbers of activated microglial cells in the substantia nigra pars compacta that were similar to those of the subacute MPTP treatment group. These results indicate that microglial activation seems to be induced mainly by the toxic effects of MPTP and that it does not further progress once the toxin administration has been terminated. This suggests that the progressive degeneration of nigral cells in Parkinson disease may not necessarily be associated with progressively increased microglial activation.
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