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Regulation of cellular proliferation in chronic neurodegenerative disease: Microglial proliferation and neurogenesis in prion disease

Final Report Summary - PRONEURODEG (Regulation of cellular proliferation in chronic neurodegenerative disease: Microglial proliferation and neurogenesis in prion disease)

The initial objectives for this project included the study of the regulation of the proliferative responses in prion disease, with a special focus on the microglial and neural stem cell (NSCs) population. During the lifetime of the Fellowship we have successfully completed the proposed objectives and also opened new avenues for future research.
As summarized in a recently published article (Gomez-Nicola et al., J Neuroscience, 2013), we have defined the temporal and spatial dynamics of microglial proliferation in prion disease, as well as describe the molecular components of the pathway controlling this process. Our results highlight the prominent activity of the system of the CSF1 receptor (CSF1R) and its ligands (CSF1 and IL34) in controlling microglial proliferation during chronic neurodegeneration. We have been able to selectively target the activation of CSF1R with a small-molecule inhibitor delivered systemically, slowed the onset of the clinical and pathological course of prion disease, and extending survival. We also showed the contribution of circulating progenitors to the microglial pool to be minimal, using a combination of tracing techniques and genetically-modified mice (CCR2-/-)(manuscript in preparation). During the Fellowship, both Prof. Perry and Dr. Gomez-Nicola, in collaboration with Prof. Holscher (University of Ulster), secured funding for a pilot grant of Alzheimer’s Research UK (ARUK) to study the microglial proliferative response in experimental models of Alzheimer’s Disease (AD) and in human post-mortem samples. This ongoing project (end date March 2014) is providing valuable information to link the results obtained with the animal model of prion disease with the most common form of dementia, AD. These results open new avenues into the understanding fundamental aspects of microglial physiology and the modulation of the innate immune response during chronic neurodegeneration.
The results from the Fellowship have provided the seed for further collaboration with internationally recognized research groups to study microglial proliferation in other models of brain disease. For example, in collaboration with Prof. Navarro (University of Barcelona), we are studying the therapeutic potential of the modulation of the activity of CSF1R in an experimental model of Amyotrophic Lateral Sclerosis. We are also exploring alternative therapeutic approaches to target CSF1R, in collaboration with industrial partners. On the basis of the results from studying microglial proliferation in prion disease, Dr. Gomez-Nicola successfully secured a prestigious New Investigator Grant from the Medical Research Council, which formally starts his career as independent investigator at the University of Southampton.
Our proposed work also aimed at studying the regulation of neurogenesis during prion disease progression. We have described the temporal dynamics of cell proliferation and generation of new cells at the two neurogenic niches: the subventricular zone and the subgranular layer of the dentate gyrus. Our findings support an active pro-neurogenic activity during the progression of prion disease, with the generation of adult-born neurons. During the lifetime of the fellowship we set up collaboration with Prof. Fehse and Dr. Riecken (University of Hamburg), to initiate RGB multicolour marking with viral vectors into the study of neurosciences. As a result of this collaboration we created a novel toolbox of γ-retro- and lenti-viral vectors to label and genetically modify newborn cells and mature neurons (Gomez-Nicola, Riecken, et al., under review). The use of RGB marking, when applied to the study of adult neurogenesis in prion disease provided novel insights into the maturation and integration of newborn cells in the dentate gyrus. We were able to provide evidence supporting that new cells complete an aberrant maturation process, affecting their integration into the network, analysed both by morphological and electrophysiological means (in collaboration with Dr. Vargas-Caballero, University of Southampton). We were also able to analyse adult neurogenesis in post-mortem samples from variant Creutzfeldt-Jakob disease (vCJD) and AD cases, with findings in accord with those obtained in the experimental model of prion disease. These results on the regulation of adult neurogenesis in prion disease are now being complemented with a study with electron microscopy, in collaboration with Prof. Garcia-Verdugo (University of Valencia), before being sent out for publication.
As a final and unifying part of the fellowship we proposed to study the impact of the innate immune response generated during prion disease on the regulation of adult neurogenesis. Although we initially proposed a series of in-vitro experiments to study this interaction, we decided to use an in-vivo approach, given our technical success in modulating microglial activity in prion disease. Using a CSF1R small molecule inhibitor, GW2580, able to decrease microglial proliferation and activation in prion disease (Gomez-Nicola et al., J Neuroscience, 2013), we studied the impact of this population on hippocampal neurogenesis. Our results support an anti-neurogenic inhibitory activity of microglia in the context of chronic neurodegeneration, corroborated with retroviral tracing techniques. Using a meta-analysis of available gene expression data in models of prion disease, we defined a list of candidate molecular regulators of neurogenesis, which was validated by qPCR in microdissected samples from the dentate gyrus. Using the microglial-inhibitory activity of GW2580 we were able to dissect which neurogenesis-regulating molecules had a microglia origin, and we are now designing new experiments aiming at modifying the activity of the pathways involved, in order to define potential therapeutic targets.

To summarize, the research aims of this fellowship has provided valuable insights into the understanding of basic mechanisms regulating the progression of chronic neurodegeneration. The results and their impact on the field will lead to the publication of a significant number of research papers in the near future, in addition to the presentations the data at international meetings performed over the past years. The completion of this project in the context of a Marie Curie fellowship provided very valuable support to Dr. Gomez-Nicola to grow and mature as a scientist and to progress into the next step of his scientific career, establishing himself as independent investigator at the Centre for Biological Sciences of the University of Southampton.