Regulation of microglial proliferation and its contribution to chronic neurodegeneration

It is well known that systemic inflammation or infection communicates with the brain and leads to the symptoms associated with illness. In people with degenerative diseases of the brain such as Alzheimer's disease there is a growing body of evidence to show that systemic infections or inflammation may accelerate disease progression and exacerbate symptoms. Communication between systemic inflammation and the brain involves the macrophage populations of the brain, those that lie at the interface of the blood vessels and coverings of the brain and the macrophages within the brain tissue itself, the microglia. In a diseased brain we have shown that these cells increase in number and are more sensitive to the systemic inflammation: they are "primed". In response to systemic inflammation they generate inflammatory molecules that have the capacity to interfere with signalling between neurons and even kill endangered neurons. The planned outcomes of the proposed project include the understanding of fundamental mechanisms that regulate immune-to-brain communication and the progression of chronic neurodegeneration, leading to the potential for development of protective or therapeutic approaches against these diseases.
In this project we will determine where the increased number of macrophages and microglia in brains with neurodegenerative disease come from: are they derived from the blood or from local proliferation. In animal models of chronic neurodegeneration we have preliminary data to show that proliferation during chronic neurodegeneration is driven through a receptor on the microglia called CSF1R. Also, there is evidence supporting the idea that activation of macrophages through this receptor also leads to priming. These two key biological functions of CSF1R, the control of proliferation and priming, would highlight the importance of this molecular pathway during chronic neurodegeneration. We will use a novel technique to deliver viral vectors to the bone marrow to label blood derived macrophages and determine whether they contribute to the macrophages and microglia in the normal and diseased brain. We will investigate whether systemic inflammation also drives proliferation and or recruitment of macrophages/microglia in healthy and diseased brains by influencing the activation of CSF1R. We will correlate our findings in animal models with studies of human brains from individuals with Alzheimer's disease who died with or without a systemic infection. We will finally investigate whether pharmacological blockade of the CSF1R can prevent both priming and proliferation of the macrophages and microglia and thus ameliorate the harmful effects of systemic inflammation on the diseased brain. The research objectives proposed here are a novel and ambitious approach to understanding inflammation in neurodegenerative diseases, and would generate important information for the neuroimmunological and medical sciences community.
The understanding of microglial biology during neurodegenerative disease is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease. The potential outcomes of the proposed research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with this disease.

A growing body of evidence suggests that systemic inflammation may contribute to the progression of chronic neurodegeneration and the exacerbation of symptoms. We have proposed that signals generated during neurodegeneration prime microglia and exaggerate their response to systemic inflammation. Here we will characterise and target one of the most prominent innate immune activities: the control of microglial proliferation and priming. We hypothesise that priming and proliferation of macrophages and microglia in the brain are intimately related. We will use the delivery of novel RGB viral vectors (collaborators in Hamburg) to the bone marrow using X-ray guidance (collaborators in Southampton), to identify the recruitment of BM cells to the perivascular, meningeal or microglia populations. We will do this in naïve animals, in animals with neurodegeneration, those with systemic inflammation and when these are combined. We will investigate how neurodegeneration in combination with systemic inflammation drives proliferation of recruited or local macrophage populations focussing on the induction of the mitogenic signalling pathways. We will use animal models of neurodegeneration: the ME7 model of prion disease and the APP PS1 transgenic model of Alzheimer's disease. We will correlate our findings with the study of human tissue from AD patients who have died with or without systemic inflammation. To address the contribution of the CSF1R pathway to proliferation and priming we will use an inhibitor of the CSF1R tyrosine kinase activity and assess the impact using behavioural, cellular, molecular and histopathological assays.
The proposed multidisciplinary and collaborative research plan will provide novel insights into the understanding of the innate immune response in chronic neurodegeneration and characterize microglial proliferation, identify molecular targets and design and analyse therapeutic approaches to control the progression of neurodegenerative diseases.

The proposed project has a high potential to reach not only a scientific but also a socio-economic impact. As highlighted by the WHO, the economic and societal burden of neurological disorders has been seriously underestimated. Mental and neurological disorders account for almost 11 per cent of disease burden the world over. In the UK 750,000 people have some form of dementia, and this number is expected to double in the next thirty years, not only affecting patients memory, activity, personality and behaviour, but also compromising their families daily life with a significant economic impact on society. The planned outcomes of the proposed project include the understanding of fundamental mechanisms that may contribute to the exacerbation of symptoms and progression of chronic neurodegeneration, leading to the potential for development of protective or therapeutic approaches against these diseases. Therefore, the proposed research plan would contribute both at identifying biomarkers of Alzheimer's disease progression and at developing an effective targeting of the innate immune response, which will help to reduce the impact of systemic comorbidities and associated inflammatory response on the diseased brain. We are ambitious and hope to provide effective ways to tackle the progression of chronic neurodegeneration, which in turn may have a beneficial impact on the daily life of dementia patients and providing novel therapeutic tools to the health system.
The development of new therapeutics to fight chronic neurodegeneration is a major area within the pharmaceutical industry. Since this project will provide evidence for potential immunomodulatory therapy of Alzheimer's or prion disease it is of substantial interest to the industry, as no current therapeutic approach exists to target the progression of chronic neurodegeneration. We propose targeting the activation of the CSF1R by small-molecule blockers, which is already being the focus of interest to target other diseases such as inflammatory arthritis, multiple sclerosis, encephalomyelitis and diverse cancers. We therefore aim at modulating the biological activity of a system involved in the progression of diverse pathological conditions, offering new avenues to develop collaborations with the pharmaceutical industry. The successful achievement of the proposed aims will in principle provide a starting point for other preclinical studies or clinical trial, as well as for the design and evaluation of new therapies.
In our opinion, being able to develop a cutting-edge research program in dementia is a privileged position and will enable us to to deliver our message to a lay audience and to the future generation of scientists. We are part of the ARUK Southampton Network, interacting with the community of dementia patients and their families, being in a position to have an impact on their understanding of the research that is being done in the labs, as well as receiving feedback to better tailor our future scientific aims. We plan to also communicate our findings to the broad community in open events like the Science Day, which allows person to person contact and discussion and integration of scientific research into society. Furthermore, and given our privileged access to University students, we aim at providing inspiration for the next generations of scientists. We will deliver our ideas and finding in lectures and workshops, as well as fostering short-term stays in our labs to participate in small research projects, making new vocations and ideas arise and push forward the advancement of science.