Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson’s Disease

Parkinson’s disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results

Thrombotic Distal Middle Cerebral Artery Occlusion Produced By Topical Fecl3 Application: A Novel Model Suitable For Intravital Microscopy And Thrombolysis Studies

Intravital or multiphoton microscopy and laser-speckle imaging have become popular because they allow live monitoring of several processes during cerebral ischemia. Available rodent models have limitations for these experiments; e. g., filament occlusion of the proximal middle cerebral artery (MCA) is difficult to perform under a microscope, whereas distal occlusion methods may damage the MCA and the peri-arterial cortex. We found that placement of a 10% FeCl3-soaked filter paper strip (0.3 x 1 mm(2)) on the duramater over the trunk of the distal MCA through a cranial window for 3 minutes induced intraarterial thrombus without damaging the peri-arterial cortex in the mouse. This caused a rapid regional cerebral blood flow decrease within 10 minutes and total occlusion of the MCA segment under the filter paper in 17 +/- 2 minutes, which resulted in a typical cortical infarct of 27 +/- 4 mm(3) at 24 hours and moderate sensorimotor deficits. There was no significant hemispheric swelling or hemorrhage or mortality at 24 hours. Reperfusion was obtained in half of the mice with tissue plasminogen activator, which allowed live monitoring of clot lysis along with restoration of tissue perfusion and MCA flow. In conclusion, this relatively simple and noninvasive stroke model is easy to perform under a microscope, making it suitable for live imaging and thrombolysis astudies. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1452-1460; doi:10.1038/jcbfm.2011.8; published online 16 February 2011WoSScopu

Individual-based predominance of visual input in multisensorial integration for balance is correlated with proprioceptive drift in rubber hand illusion

Abstract Rubber hand illusion (RHI) is a traditional task that examines multisensory integration. The visual capture of tactile stimulus given to the seen rubber hand was considered to predominate the sensory processing and interfere with the bottom-up proprioceptive and tactile inputs received from the unseen real hand that results in mislocalization of participants hand towards rubber hand, namely proprioceptive drift (PD). Another task that requires multisensorial integration and shows a predominance of visual input is the maintenance of body posture. However, if the predominance of visual input in one task is generalizable to another task is yet to be elucidated. We aimed to examine if individual dependency on visual inputs in multisensorial integration in balance correlated with PD in RHI. Twenty healthy participants were recruited for the study and completed the RHI task. The contribution of visual inputs to the static body balance was measured with the instrumented clinical test of sensory interaction for balance and indexed with Romberg Quotient (RQ). We found a moderate positive correlation between PD and RQ. Individuals with more dependence on visual information in maintaining body posture had higher PD in RHI. Our results indicate that there can be an individual-based dependence on particular domains of sensory input preserved during different tasks of multisensorial integration. Future studies must clarify whether this tendency relates to certain physical or physiological traits

Alpha-Synuclein Aggregation Induced By Brief Ischemia Negatively Impacts Neuronal Survival in Vivo: A Study in [A30P] Alpha-Synuclein Transgenic Mouse

Alpha-synuclein oligomerization and aggregation are considered to have a role in the pathogenesis of neurodegenerative diseases. However, despite numerous in vitro studies, the impact of aggregates in the intact brain is unclear. In vitro, oxidative/nitrative stress and acidity induce alpha-synuclein oligomerization. These conditions favoring alpha-synuclein fibrillization are present in the ischemic brain, which may serve as an in vivo model to study alpha-synuclein aggregation. In this study, we show that 30-minute proximal middle cerebral artery (MCA) occlusion and 72 hours reperfusion induce oligomerization of wild-type alpha-synuclein in the ischemic mouse brain. The nonamyloidogenic isoform beta-synuclein did not form oligomers. Alpha-synuclein aggregates were confined to neurons and colocalized with ubiquitin immunoreactivity. We also found that 30 minutes proximal MCA occlusion and 24 hours reperfusion induced larger infarcts in C57BL/6(Thy1)-h[A30P]alphaSYN transgenic mice, which have an increased tendency to form synuclein fibrils. Trangenics also developed more selective neuronal necrosis when subjected to 20 minutes distal MCA occlusion and 72 hours reperfusion. Enhanced 3-nitrotyrosine immunoreactivity in transgenic mice suggests that oxidative/nitrative stress may be one of the mechanisms mediating aggregate toxicity. Thus, the increased vulnerability of transgenic mice to ischemia suggests that alpha-synuclein aggregates not only form during ischemia but also negatively impact neuronal survival, supporting the idea that alpha-synuclein misfolding may be neurotoxic. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 913-923; doi:10.1038/jcbfm.2010.170; published online 29 September 2010WoSScopu

The Presence of Autoantibodies Against Vascular and Nervous Tissue in Sera From Patients with Neuro-Behçet's Disease

ABSTRACT Introduction: Behçet's disease is a chronic inflammatory disease of unknown aetiology that affects multiple organ systems. Since the diagnosis of this disease mainly relies on clinical criteria, a diagnostic laboratory test is required especially for neuro-Behçet's patients without systemic involvement

Impact of Autoimmune Demyelinating Brain Disease Sera on Pericyte Survival

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by demyelination and brain pericyte dysfunction might be involved in MS pathogenesis Our aim was to evaluate whether the factors in serum affect pericyte survival. METHOD: C57BL/6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce experimental autoimmune encephalomyelitis (EAE). To confirm the animal model, the sera level of anti-MOG antibody in mice and platelet-derived growth factor-BB (PDGF-BB) in patients was measured by ELISA. Human brain vascular pericytes (HBVP) cell lines were incubated with sera of EAE mice and primer progressive MS (PPMS), seconder progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients. The viability of HBVP is measured with Annexin V-FITC/propidium iodide staining with flow cytometry. RESULTS: Annexin V-FITC/propidium iodide staining with flow cytometry showed increased ratios of early apoptosis and decreased survival following incubation with sera of EAE and progressive MS. Levels of platelet-derived growth factor-BB were identical in serum and cerebrospinal fluids of patients with different forms of MS. CONCLUSION: Our results suggest that serum factors might contribute to progressive MS pathogenesis via pericyte dysfunction