Central and Peripheral Inflammation: Connecting the Immune Responses of Parkinson's Disease.

Inflammation has increasingly become a focus of study in regards to Parkinson's disease (PD). Moreover, both central and peripheral sources of inflammation have been implicated in the pathogenesis of PD. Central inflammation consisting of activated microglia, astroglia, and T cell responses within the PD central nervous system; and peripheral inflammation referring to activated innate cells and T cell signaling in the enteric nervous system, gastrointestinal tract, and blood. This review will highlight important work that further implicates central and peripheral inflammation in playing a role in PD. We also discuss how these two distant inflammations appear related and how that may be mediated by autoantigenic responses to α-syn.

Gut microbiome-mediated regulation of neuroinflammation.

The intestinal microbiome influences neuroinflammatory disease in animal models, and recent studies have identified multiple pathways of communication between the gut and brain. Microbes are able to produce metabolites that enter circulation, can alter inflammatory tone in the intestines, periphery, and central nervous system (CNS), and affect trafficking of immune cells into the brain. Additionally, the vagus nerve that connects the enteric nervous system to the CNS is implicated in modulation of brain immune responses. As preclinical research findings and concepts are applied to humans, the potential impacts of the gut microbiome-brain axis on neuroinflammation represent exciting frontiers for further investigation.

CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease.

α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson's disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson's disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRß or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson's disease and that targeting these T cell responses could be an avenue for disease modifying treatments.

Innate and adaptive immune responses in Parkinson's disease.

Parkinson's disease (PD) has classically been defined as a movement disorder, in which motor symptoms are explained by the aggregation of alpha-synuclein (α-syn) and subsequent death of dopaminergic neurons of the substantia nigra pars compacta (SNpc). More recently, the multisystem effects of the disease have been investigated, with the immune system being implicated in a number of these processes in the brain, the blood, and the gut. In this review, we highlight the dysfunctional immune system found in both human PD and animal models of the disease, and discuss how genetic risk factors and risk modifiers are associated with pro-inflammatory immune responses. Finally, we emphasize evidence that the immune response drives the pathogenesis and progression of PD, and discuss key questions that remain to be investigated in order to identify immunomodulatory therapies in PD.

T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR+ microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3+, CD4+, and CD8+ T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-ß or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by intracellular alpha-synuclein (α-syn) inclusions, progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and activation of the innate and adaptive immune systems. Disruption of immune signaling between the central nervous system (CNS) and periphery, such as through targeting the chemokine receptor type 2 (CCR2) or the major histocompatibility complex II (MHCII), is neuroprotective in rodent models of PD, suggesting a key role for innate and adaptive immunity in disease progression. The purpose of this study was to investigate whether genetic knockout or RNA silencing of the class II transactivator (CIITA), a transcriptional co-activator required for MHCII induction, is effective in reducing the neuroinflammation and neurodegeneration observed in an α-syn mouse model of PD. METHODS: In vitro, we utilized microglia cultures from WT or CIITA -/- mice treated with α-syn fibrils to investigate inflammatory iNOS expression and antigen processing via immunocytochemistry (ICC). In vivo, an adeno-associated virus (AAV) was used to overexpress α-syn in WT and CIITA -/- mice as a model for PD. Concurrently with AAV-mediated overexpression of α-syn, WT mice received CIITA-targeted shRNAs packaged in lentiviral constructs. Immunohistochemistry and flow cytometry were used to assess inflammation and peripheral cell infiltration at 4 weeks post transduction, and unbiased stereology was used 6 months post transduction to assess neurodegeneration. RESULTS: Using ICC and DQ-ovalbumin, we show that CIITA -/- microglial cultures failed to upregulate iNOS and MHCII expression, and had decreased antigen processing in response to α-syn fibrils when compared to WT microglia. In vivo, global knock-out of CIITA as well as local knockdown using lentiviral shRNAs targeting CIITA attenuated MHCII expression, peripheral immune cell infiltration, and α-syn-induced neurodegeneration. CONCLUSION: Our data provide evidence that CIITA is required for α-syn-induced MHCII induction and subsequent infiltration of peripheral immune cells in an α-syn mouse model of PD. Additionally, we demonstrate that CIITA in the CNS drives neuroinflammation and neurodegeneration. These data provide further support that the disruption or modulation of antigen processing and presentation via CIITA is a promising target for therapeutic development in preclinical animal models of PD.

Examining the contributions of desirable difficulty and reminding to the spacing effect.

Although substantial evidence indicates that spacing repeated study events with intervening material generally enhances memory performance relative to massing study events, the mechanism underlying this benefit is less clear. Two experiments examined the role of reminding difficulty during the acquisition of material in modulating final memory performance for spaced repetitions utilizing recognition (Experiment 1) and recall tests (Experiment 2). Specifically, participants studied a list of words presented one or two times separated by one or five items. On each trial participants reported whether the item had been previously presented (i.e., repetition detection judgment), and the response latency served as a proxy for reminding difficulty such that longer response latencies reflected more difficult reminding. A third experiment extended this paradigm with the inclusion of a massed condition and novel lag conditions (three and ten items). Results revealed significant lag effects in final test performance across experiments despite comparable repetition detection difficulty between lag conditions during acquisition. Moreover, results from within-participant point-biserial analyses and mediation analyses converged on overall performance measures in suggesting that repetition detection difficulty failed to modulate final test performance in the current paradigm. Discussion considers the implications of the current results for mechanisms proposed to underlie the benefits of spaced study and spaced retrieval practice.

Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease.

Accumulation of alpha-synuclein (α-syn) in the central nervous system (CNS) is a core feature of Parkinson disease (PD) that leads to activation of the innate immune system, production of inflammatory cytokines and chemokines, and subsequent neurodegeneration. Here, we used heterozygous reporter knock-in mice in which the first exons of the fractalkine receptor (CX3CR1) and of the C-C chemokine receptor type 2 (CCR2) are replaced with fluorescent reporters to study the role of resident microglia (CX3CR1+) and infiltrating peripheral monocytes (CCR2+), respectively, in the CNS. We used an α-syn mouse model induced by viral over-expression of α-syn. We find that in vivo, expression of full-length human α-syn induces robust infiltration of pro-inflammatory CCR2+ peripheral monocytes into the substantia nigra. Genetic deletion of CCR2 prevents α-syn induced monocyte entry, attenuates MHCII expression and blocks the subsequent degeneration of dopaminergic neurons. These results demonstrate that extravasation of pro-inflammatory peripheral monocytes into the CNS plays a key role in neurodegeneration in this model of PD synucleinopathy, and suggest that peripheral monocytes may be a target of neuroprotective therapies for human PD.