Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages, different subtypes of the disease are distinguished by their predominant parkinsonian or cerebellar symptoms, reflecting its heterogeneous nature. The pathognomonic feature of multiple system atrophy is the presence of α-synuclein (αSyn) protein deposits in oligodendroglial cells. αSyn can assemble in specific cellular or disease environments and form αSyn strains with unique structural features, but the ability of αSyn strains to propagate in oligodendrocytes remains elusive. Recently, it was shown that αSyn strains with related conformations exist in the brains of patients. Here, we investigated whether different αSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant αSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that they determined disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. αSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagated oligodendroglial inclusions that were structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions, in the brains of patients with multiple system atrophy. This study, therefore, shows that the multiple system atrophy phenotype is governed by both the nature of the αSyn strain and the host environment and that by injecting αSyn strains into an animal model of the disease, a more comprehensive phenotype can be established.

The development of disease-modifying therapies for Parkinson’s disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson’s disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein–induced neurotoxicity and neuroinflammation in preclinical Parkinson’s disease models have reported conflicting results. Here, we aimed to further explore the functional interaction between α-synuclein and LRRK2 and to evaluate the therapeutic potential of targeting physiological LRRK2 levels. We studied the effects of total LRRK2 protein loss as well as pharmacological LRRK2 kinase inhibition in viral vector–mediated α-synuclein–based Parkinson’s disease models developing early- and late-stage neurodegeneration. Surprisingly, total LRRK2 ablation or in-diet treatment with the LRRK2 kinase inhibitor MLi-2 did not significantly modify α-synuclein–induced motor deficits, dopaminergic cell loss, or α-synuclein pathology. Interestingly, we found a significant effect on α-synuclein–induced neuroinflammatory changes in the absence of LRRK2, with a reduced microglial activation and CD4+ and CD8+ T cell infiltration. This observed lack of protection against α-synuclein–induced toxicity should be well considered in light of the ongoing therapeutic development of LRRK2 kinase inhibitors for idiopathic Parkinson’s disease. Future studies will be crucial to understand the link between these neuroinflammatory processes and disease progression as well as the role of α-synuclein and LRRK2 in these pathological events.

During the pathogenesis of Parkinson's disease (PD), aggregation of alpha-synuclein (αSyn) induces a vicious cycle of cellular impairments that lead to neurodegeneration. Consequently, removing toxic αSyn aggregates constitutes a plausible strategy against PD. In this work, we tested whether stimulating the autolysosomal degradation of αSyn aggregates through the Ras-related in brain 7 (Rab7) pathway can reverse αSyn-induced cellular impairment and prevent neurodegeneration in vivo. The disease-related A53T mutant of αSyn was expressed in primary neurons and in dopaminergic neurons of the rat brain simultaneously with wild type (WT) Rab7 or the T22N mutant as negative control. The cellular integrity was quantified by morphological and biochemical analyses. In primary neurons, WT Rab7 rescued the αSyn-induced loss of neurons and neurites. Furthermore, Rab7 decreased the amount of reactive oxygen species and the amount of Triton X-100 insoluble αSyn. In rat brain, WT Rab7 reduced αSyn-induced loss of dopaminergic axon terminals in the striatum and the loss of dopaminergic dendrites in the substantia nigra pars reticulata. Further, WT Rab7 lowered αSyn pathology as quantified by phosphorylated αSyn staining. Finally, WT Rab7 attenuated αSyn-induced DNA damage in primary neurons and rat brain. In brief, Rab7 reduced αSyn-induced pathology, ameliorated αSyn-induced neuronal degeneration, oxidative stress and DNA damage. These findings indicate that Rab7 is able to disrupt the vicious cycle of cellular impairment, αSyn pathology and neurodegeneration present in PD. Stimulation of Rab7 and the autolysosomal degradation pathway could therefore constitute a beneficial strategy for PD.

Synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease with prominent autonomic and motor features. Different disease subtypes are distinguished by their predominant parkinsonian or cerebellar signs. The pathognomonic feature of MSA is the presence of α-synuclein (αSyn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with αSyn pathology, is clinically so heterogeneous, why it progresses at varying rates and how neuroinflammation affects disease progression. Recently, it was shown that different strains of αSyn can assemble in unique disease environments but also that a variety of strains might exist in the brain of MSA patients. We therefore investigated if different αSyn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of αSyn in MSA transgenic mice and found that they significantly impact MSA disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo . By injecting αSyn strains in MSA mice we could more closely mimic a comprehensive MSA phenotype in an experimental setting. This study therefore shows that i) MSA phenotype is governed by both the αSyn strain nature and the host environment and ii) αSyn strains can directly trigger a detrimental immune response related to disease progression in MSA.

We investigated the glucose metabolism in an adeno-associated viral vector based alpha-synuclein rat model for Parkinson’s disease (PD) using longitudinal 18 F-FDG PET imaging, which resulted in an improved characterization of this animal model. We generated a PD specific pattern (PDSP) based on a multivariate classification approach to differentiate between a PD and control group at a late disease stage, where the neurodegeneration is considered nearly complete. In particular, we applied a principal component analysis prior to classification by a support vector machine (SVM). Moreover, by using a SVM for regression to predict corresponding motor scores, a PD motor pattern (PDMP) was derived as well. The PDSP mainly corresponds to the PDMP and overlaps to a large extent with the human pattern. We were able to quantify disease expression at previous time points by projecting onto the PDSP and PDMP. While a univariate analysis indicated metabolic changes which did not persist through time, both PDSP and PDMP were able to differentiate significantly (p-value < 0.05) between the PD and control group at week 4, 6 and 9 post injection, while no significant differences were obtained at baseline and at week 3, which is in accordance with the animal model.

Event Abstract Back to Event NEURONAL ACTIVITY MODULATION IN AN ALPHA-SYNUCLEIN-BASED RAT MODEL FOR PARKINSON’S DISEASE. Teresa Torre1, 2*, Jens Devoght3, 4, Chris Van Den Haute1, 2, Bert Brône3, 4, Anke Van Der Perren1, 2 and Veerle Baekelandt1, 2* 1 KU Leuven, Belgium 2 Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Belgium 3 Biomedical Research Institute, Faculty of Medicine and Life Sciences, University of Hasselt, Belgium 4 BIOMED, Belgium Objectives. The general aim of this study was to investigate the effect of neuromodulation on Parkinson’s disease (PD) pathogenesis. More specifically, we aimed to investigate the relationship between neuronal activity, motor behaviour, alpha-synuclein (αSYN) aggregation and dopaminergic neurodegeneration in a viral vector-based αSYN rat model. Methods. To modulate the neuronal activity we used a chemogenetic tool, namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Both αSYN and the DREADDS were overexpressed in the substantia nigra (SN) of the rat using rAAV vectors. We validated the changes in neuronal activity in response to intraperitoneal injection of the agonist clozapine-N-oxide (CNO) using c-fos immunostaining and electrophysiological recordings. CNO was administered for … weeks (indicate time period). Motor performance was assessed using the cylinder test at 1, 2 and 4 weeks after injection. Dopaminergic neurodegeneration and αSYN aggregation were evaluated by immunohistological stainings and biochemical characterization. Results. We found that chronic activation of dopaminergic neurons worsens the motor behaviour in our rAAV-based αSYN rat model. Nevertheless, no significant differences in neuronal cell loss were observed between the chronically stimulated animals and the controls. We are currently investigating differences in αSYN aggregation and phosphorylation. Conclusions. Neuronal modulation appears to aggravate the motor behavioural deficits caused by αSYN overexpression in a viral vector-based rat model. In depth characterization using immunohistochemical and biochemical analysis is currently ongoing to understand the molecular cause of these behavioural changes. Objectives. The general aim of this study was to investigate the effect of neuromodulation on Parkinson’s disease (PD) pathogenesis. More specifically, we aimed to investigate the relationship between neuronal activity, motor behaviour, alpha-synuclein (αSYN) aggregation and dopaminergic neurodegeneration in a viral vector-based αSYN rat model. Methods. To modulate the neuronal activity we used a chemogenetic tool, namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Both αSYN and the DREADDS were overexpressed in the substantia nigra (SN) of the rat using rAAV vectors. We validated the changes in neuronal activity in response to intraperitoneal injection of the agonist clozapine-N-oxide (CNO) using c-fos immunostaining and electrophysiological recordings. CNO was administered for 3 weeks. Motor performance was assessed using the cylinder test at 1, 2 and 4 weeks after injection. Dopaminergic neurodegeneration and αSYN aggregation were evaluated by immunohistological stainings and biochemical characterization. Results. We found that chronic activation of dopaminergic neurons worsens the motor behaviour in our rAAV-based αSYN rat model. Nevertheless, no significant differences in neuronal cell loss were observed between the chronically stimulated animals and the controls. We are currently investigating differences in αSYN aggregation and phosphorylation. Conclusions. Neuronal modulation appears to aggravate the motor behavioural deficits caused by αSYN overexpression in a viral vector-based rat model. In depth characterization using immunohistochemical and biochemical analysis is currently ongoing to understand the molecular cause of these behavioural changes. Keywords: synuclein alpha (SNCA), Neuromodulation, DREADDs, synaptic activity, Parkinson ' s disease Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019. Presentation Type: Poster presentation Topic: Behavioral/Systems Neuroscience Citation: Torre T, Devoght J, Van Den Haute C, Brône B, Van Der Perren A and Baekelandt V (2019). NEURONAL ACTIVITY MODULATION IN AN ALPHA-SYNUCLEIN-BASED RAT MODEL FOR PARKINSON’S DISEASE.. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00006 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 01 May 2019; Published Online: 27 Sep 2019. * Correspondence: Miss. Teresa Torre, KU Leuven, Leuven, Belgium, ttorremuruzabal@gmail.com Prof. Veerle Baekelandt, KU Leuven, Leuven, Belgium, veerle.baekelandt@kuleuven.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Teresa Torre Jens Devoght Chris Van Den Haute Bert Brône Anke Van Der Perren Veerle Baekelandt Google Teresa Torre Jens Devoght Chris Van Den Haute Bert Brône Anke Van Der Perren Veerle Baekelandt Google Scholar Teresa Torre Jens Devoght Chris Van Den Haute Bert Brône Anke Van Der Perren Veerle Baekelandt PubMed Teresa Torre Jens Devoght Chris Van Den Haute Bert Brône Anke Van Der Perren Veerle Baekelandt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson’s disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T α-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by α-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of α-SYN, linking neuronal activity to the pathophysiological role of α-SYN in PD.

The purinergic P2X7 receptor is a key mediator in (neuro)inflammation, a process that is associated with neurodegeneration and excitotoxicity in Parkinson's disease (PD). Recently, P2X7 imaging has become possible with [11C]JNJ-(54173)717. We investigated P2X7 availability, in comparison with availability of the translocator protein (TSPO), in two well-characterized rat models of PD using in vitro autoradiography at multiple time points throughout the disease progression. Rats received either a unilateral injection with 6-hydroxydopamine (6-OHDA) in the striatum, or with recombinant adeno-associated viral vector overexpressing human A53T alpha-synuclein (α-SYN) in the substantia nigra. Transverse cryosections were incubated with [11C]JNJ-717 for P2X7 or [18F]DPA-714 for TSPO. [11C]JNJ-717 binding ratios were transiently elevated in the striatum of 6-OHDA rats at day 14-28 post-injection, with peak P2X7 binding at day 14. This largely coincided with the time course of striatal [18F]DPA-714 binding which was elevated at day 7-21, with peak TSPO binding at day 7. Increased P2X7 availability co-localized with microglial, but not astrocyte or neuronal markers. In the chronic α-SYN model, no significant differences were found in P2X7 binding, although in vitro TSPO overexpression was reported previously. This first study showed an increased P2X7 availability in the acute PD model in a time window corresponding with elevated TSPO binding and motor behavior changes. In contrast, the dynamics of TSPO and P2X7 were divergent in the chronic α-SYN model where no P2X7 changes were detectable. Overall, extended P2X7 phenotyping is warranted prior to implementation of P2X7 imaging for monitoring of neuroinflammation.

Innate immune activation and chronic neuroinflammation are characteristic features of many neurodegenerative diseases including Parkinson's disease (PD) and may contribute to the pathophysiology of the disease. The discovery of misfolded alpha-synuclein (αSYN) protein aggregates, which amplify in a “prion-like” fashion, has led us to consider that pathogenic αSYN might be hijacking the activation and mobilization mechanism of the peripheral immune system to reach and disseminate within the CNS. Furthermore, our lab and other groups have recently shown that αSYN can adopt distinct fibril conformations or “strains” with varying levels of pathogenic impact. Therefore, the aim of this study was to assess the impact of peripheral inflammation on αSYN spreading in order to better understand the participation of the immune system in the progression of PD. The results presented here show that intraperitoneal LPS injection prior to systemic intravenous recombinant administration of two different αSYN pathogenic strains (fibrils or ribbons) in wild type mice, induces an increase in brain resident microglia and promotes the recruitment of leukocytes toward the brain and the spinal cord. Our findings show for the first time that αSYN can be internalized by LPS-primed inflammatory monocytes, which in turn favors the dissemination from the periphery toward the brain and spinal cord. Further, we found a differential recruitment of CD4+ and CD8+ T cells after LPS priming and subsequent administration of the αSYN ribbons strain. Together, these data argue for a role of the peripheral immune system in αSYN pathology.

Event Abstract Back to Event The role of LRRK2 inhibition in α-synuclein-induced neurotoxicity and neuroinflammation in vivo. Diego Cabezudo1*, Anke Van Der Perren1, Géraldine Gelders1, Chris Van Den Haute1, Veerle Baekelandt1 and Evy Lobbestael1 1 KU Leuven, Belgium Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, affecting 10 million people worldwide. A major challenge is the development of disease-modifying therapies, for which a better understanding of PD pathogenesis is indispensable. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein (α-SYN) are key players in PD and previous studies indicate that targeting LRRK2 can modify α-SYN-induced neurotoxicity and neuroinflammation in preclinical PD models. To further explore the functional interaction between both proteins and evaluate the therapeutic potential of LRRK2, we studied the effects of LRRK2 kinase inhibition and total LRRK2 protein loss in different viral vector-mediated α-SYN-based PD models. We used recombinant adeno-associated viral vectors (rAAV2/7) to overexpress human wild-type or pathogenic A53T α-SYN in the substantia nigra of wild-type and LRRK2 knock out rats. By applying different vector doses, we modelled early and late stage neurodegeneration. In addition, by using an in-diet treatment protocol with MLi-2, we assessed the therapeutic potential of LRRK2 kinase inhibition. Effects on motor behaviour deficits were evaluated by the cylinder test, nigrostriatal neurodegeneration and α-SYN pathology were assessed by immunohistochemistry. Given the role of both LRRK2 and α-SYN in neuroinflammation, we also examined whether loss of LRRK2 (kinase activity) can affect α-SYN-induced neuroinflammatory changes in the different models. Keywords: LRRK2, A-synuclein, Neurodegenaration, Parkinson ' s disease, Neuroinflammantion Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019. Presentation Type: Poster presentation Topic: Cellular/Molecular Neuroscience Citation: Cabezudo D, Van Der Perren A, Gelders G, Van Den Haute C, Baekelandt V and Lobbestael E (2019). The role of LRRK2 inhibition in α-synuclein-induced neurotoxicity and neuroinflammation in vivo.. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00020 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2019; Published Online: 27 Sep 2019. * Correspondence: Mr. Diego Cabezudo, KU Leuven, Leuven, Belgium, diego.cabezudo@kuleuven.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Diego Cabezudo Anke Van Der Perren Géraldine Gelders Chris Van Den Haute Veerle Baekelandt Evy Lobbestael Google Diego Cabezudo Anke Van Der Perren Géraldine Gelders Chris Van Den Haute Veerle Baekelandt Evy Lobbestael Google Scholar Diego Cabezudo Anke Van Der Perren Géraldine Gelders Chris Van Den Haute Veerle Baekelandt Evy Lobbestael PubMed Diego Cabezudo Anke Van Der Perren Géraldine Gelders Chris Van Den Haute Veerle Baekelandt Evy Lobbestael Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Event Abstract Back to Event In vivo characterization of distinct patient-derived alpha-synuclein strains Géraldine Gelders1*, Anke Van Der Perren1*, Filipa De Brito1, Wouter Peelaerts1 and Veerle Baekelandt1 1 Department of Neurosciences, KU Leuven, Belgium Van der Perren A.1*, Gelders G.1*, Fenyi A.2*, Bousset L.2, Brito F1, Peelaerts W.1; Gentleman SM.3, Melki R.2; Baekelandt V1, 4. 1 KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium. 2 Institut Fançois Jacob (MIRCen), CEA, and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France. 3 Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK 4 KU Leuven, Leuven Viral Vector Core, Leuven, Belgium * Equal contribution Objectives: Alpha-synuclein (ɑSYN) aggregation is considered to play a central role in several neurodegenerative diseases, such as Parkinson’s disease (PD), Multiple System Atrophy (MSA) and dementia with Lewy bodies (DLB) but the exact relationship between ɑSYN aggregation and pathogenesis remains unclear. Synucleinopathies are determined by the deposition of ɑSYN aggregates but segregate in distinct pathological phenotypes and diagnostic criteria. ɑSYN was shown to assemble into different polymorphs or ‘strains’ (Bousset, 2013, Nature Comm). This has led to the hypothesis that strains might account for the distinct clinico-pathological traits within synucleinopathies (Peelaerts, 2015, Nature). The purpose of this study was to compare different ɑSYN assemblies derived from the brain of patients with PD, MSA and DLB and assess their capacities to amplify, propagate and induce neurodegeneration in vivo. Methods: Fresh human brain material, which was extensively characterized from a clinico-pathological point of view, was homogenized and used to amplify patient-derived human ɑSYN strains via a protein misfolding cyclic amplification assay (PMCA). Brain homogenates and the products of PMCA reactions were injected in the substantia nigra of wild-type rats with or without vector-based overexpression of alpha-synuclein. Animals were followed up for 5 months by behavioral analysis, after the brains were processed for histopathological analysis. Results and Conclusion: We observed striking differences between the different patient-derived strains in terms of neuropathology. The existence of ɑSYN strains could provide a basis for the heterogeneity observed in synucleinopathies and open new therapeutic opportunities such as targeting the degradation or spreading of specific αSYN assemblies. Keywords: alpha-Synuclein, Parkinson ' s disease, synucleinopathies, strains, neurodegeneration Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019. Presentation Type: Poster presentation Topic: Behavioral/Systems Neuroscience Citation: Gelders G, Van Der Perren A, De Brito F, Peelaerts W and Baekelandt V (2019). In vivo characterization of distinct patient-derived alpha-synuclein strains. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00001 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2019; Published Online: 27 Sep 2019. * Correspondence: Mrs. Géraldine Gelders, Department of Neurosciences, KU Leuven, Leuven, Belgium, geraldine.gelders@outlook.be Dr. Anke Van Der Perren, Department of Neurosciences, KU Leuven, Leuven, Belgium, anke.vanderperren@kuleuven.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Géraldine Gelders Anke Van Der Perren Filipa De Brito Wouter Peelaerts Veerle Baekelandt Google Géraldine Gelders Anke Van Der Perren Filipa De Brito Wouter Peelaerts Veerle Baekelandt Google Scholar Géraldine Gelders Anke Van Der Perren Filipa De Brito Wouter Peelaerts Veerle Baekelandt PubMed Géraldine Gelders Anke Van Der Perren Filipa De Brito Wouter Peelaerts Veerle Baekelandt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Rat models based on viral vector-mediated overexpression of a-synuclein are regarded as highly valuable models that closely mimic cardinal features of human Parkinson's disease (PD) such as L-DOPA-dependent motor impairment, dopaminergic neurodegeneration and alpha-synuclein inclusions. To date, the downstream effects of dopaminergic cell loss on brain glucose metabolism, including the neuroinflammation component, have not been phenotyped in detail for this model. Cerebral glucose metabolism was monitored throughout different stages of the disease using in vivo 2-[F-18]-fluoro-2-deoxy-D-glucose ([F-18]FDG) positron emission tomography (PET) and was combined with in vitro [F-18]DPA-714 autoradiography to assess concomitant inflammation. Rats were unilaterally injected with recombinant adeno-associated viral vector serotype 2/7 (rAAV2/7) encoding either A53T alpha-synuclein or eGFP. Brain [F-18]FDG microPET was performed at baseline, 1, 2, 3, 4, 6, and 9 weeks postsurgery, in combination with behavioral tests. As a second experiment, [F-18]DPA-714 autoradiography was executed across the same timeline. Voxel-based analysis of relative [F-18]FDG uptake showed a dynamic pattern of PD-related metabolic changes throughout the disease progression (weeks 2-9). Glucose hypermetabolism covering a large bilateral area reaching from the insular, motor- and somatosensory cortex to the striatum was observed at week 2. At week 4, hypermetabolism presented in a cluster covering the ipsilateral nigra-thalamic region, whereas hypometabolism was noted in the ipsilateral striatum at week 6. Elevated [F-18]FDG uptake was seen in a cluster extending across the contralateral striatum, motor- and somatosensory cortex at week 9. Increased [F-18]FDG in the region of the substantia nigra was associated with increased [F-18]DPA-714 binding, and correlated significantly with motor symptoms. These findings point to disease-associated metabolic and neuroinflammatory changes taking place in the primary area of dopaminergic neurodegeneration but also closely interconnected motor and somatosensory brain regions.

Neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) impose a pressing burden on our developed and consequently aging society. Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. Nevertheless, several questions remain unanswered regarding the role of misfolded protein aggregates and the cause of neuronal cell death. Recently, it has been postulated that neuroinflammatory processes might play a crucial role in the pathogenesis of PD. Numerous postmortem, brain imaging, epidemiological, and animal studies have documented the involvement of the innate and adaptive immunity in neurodegeneration. Whether these inflammatory processes are directly involved in the etiology of PD or represent secondary consequences of nigrostriatal pathway injury is the subject of intensive research. Immune alterations in response to extracellular α -synuclein may play a critical role in modulating Parkinson’s disease progression. In this review, we address the current concept of neuroinflammation and its involvement in PD-associated neurodegeneration.

Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [18F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology.

The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted.

Over the past few decades, research on Alzheimer's disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that-upon engagement of pattern recognition receptors-induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.

Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intraneuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as dangerassociated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on & Michael T. Heneka michael.heneka@ukbonn.de 1 Faculty of Medicine, Institute of Neuropathology, University of Freiburg, Freiburg, Germany 2 Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 3 Experimental Neuroinflammation Laboratory, Department of Experimental Medical Sciences, Biomedical Centrum (BMC), Lund University, Lund, Sweden 4 Department of Psychiatry and Psychotherapy, Medical Center University of Freiburg, Faculty of Medicine University of Freiburg, Freiburg, Germany 5 Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Département de la Recherche Fondamentale (DRF), Institut de biologie François Jacob, MIRCen, 92260 Fontenay-aux-Roses, France 6 Neurodegenerative Diseases Laboratory, Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, F-92260 Fontenay-aux-Roses, France 7 German Center for Neurodegenerative Diseases (DZNE), Sigmund Freud Str. 27, 53127 Bonn, Germany 8 Biomedical Centre, Institute of Innate Immunity, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany 9 Department of Neurosciences, Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium 10 Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University of Bonn Medical Center, Sigmund-Freud Str. 25, 53127 Bonn, Germany 11 Center for Neuroscience (SILS-CNS), Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands 12 Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität ErlangenNürnberg, Erlangen, Germany 13 Vita-Salute San Raffaele University, Milan, Italy 14 In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy 15 Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany 16 Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA 17 Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany 18 Pfizer Deutschland GmbH, Berlin, Germany CNS Drugs (2017) 31:1057–1082 https://doi.org/10.1007/s40263-017-0483-3

Event Abstract Back to Event Differential response of microglia to distinct alpha-synuclein assemblies Anke Van Der Perren1*, Géraldine Gelders1, Francesca Macchi1, Wouter Peelaerts1, Luc Bousset2, Chris Van Den Haute1, Ronald Melki2 and Veerle Baekelandt1 1 KU Leuven, Neurosciences, Belgium 2 Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, France Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. There is emerging evidence that these protein aggregates can adopt distinct conformations characterized by noticeable differences in phenotypic features. The discovery of the prion-like transmissible nature of these proteins suggests a pathogenic trigger which propagate throughout the nervous system underlying the progression of the disease. In addition, there is mounting evidence that neuroinflammatory processes are closely linked to neurodegeneration during ageing. In the present study, we investigated the immunological properties of different alpha-synuclein assemblies to define the role of the innate immune system in Parkinson’s disease. We examined the microglia cell response to different recombinant alpha-synuclein assemblies via exogenous addition to primary microglia cultures. We studied uptake and degradation of the different alpha-synuclein assemblies in our primary microglial cultures by confocal microscopy and western blot. The microglial status was analyzed using qPCR and ELISA. Next, we added the microglial supernatant to primary neurons to investigate the impact of microglial priming by specific alpha-synuclein assemblies on neuronal toxicity. We showed that distinct fibrillar alpha-synuclein assemblies promote a pro-inflammatory activation of microglia, however differences between fibrillar assemblies could be observed. Oligomeric species, thought to be the primary species responsible for the disease, were unable to trigger the same cascades. These results support our hypothesis that distinct fibrillar alpha-synuclein assemblies drive the pro-inflammatory activity of microglia and represent the toxic species contributing to the disease. Keywords: alpha-Synuclein, Microglia, Parkinson's disease, Neuroinflammation, synucleinopathies Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Poster Presentation Topic: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homeostatic Challenge Citation: Van Der Perren A, Gelders G, Macchi F, Peelaerts W, Bousset L, Van Den Haute C, Melki R and Baekelandt V (2019). Differential response of microglia to distinct alpha-synuclein assemblies. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00095 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: PhD. Anke Van Der Perren, KU Leuven, Neurosciences, Leuven, Belgium, anke.vanderperren@med.kuleuven.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Anke Van Der Perren Géraldine Gelders Francesca Macchi Wouter Peelaerts Luc Bousset Chris Van Den Haute Ronald Melki Veerle Baekelandt Google Anke Van Der Perren Géraldine Gelders Francesca Macchi Wouter Peelaerts Luc Bousset Chris Van Den Haute Ronald Melki Veerle Baekelandt Google Scholar Anke Van Der Perren Géraldine Gelders Francesca Macchi Wouter Peelaerts Luc Bousset Chris Van Den Haute Ronald Melki Veerle Baekelandt PubMed Anke Van Der Perren Géraldine Gelders Francesca Macchi Wouter Peelaerts Luc Bousset Chris Van Den Haute Ronald Melki Veerle Baekelandt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.