Regulation of microglial proliferation and its contribution to chronic neurodegeneration

Lead Research Organisation: University of Southampton
Department Name: School of Biological Sciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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De Lucia C (2016) Microglia regulate hippocampal neurogenesis during chronic neurodegeneration. in Brain, behavior, and immunity

 
Description Alzheimer Reseach UK Equipment Grant
Amount £38,912 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
 
Description Dementia Consortium Grant
Amount £209,145 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 10/2017
 
Description Leverhulme Trust research grant
Amount £236,866 (GBP)
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description MRC responsive mode
Amount £583,321 (GBP)
Funding ID MR/P024572/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
Title In-vivo cell tracking and genetic modification with LeGO RGB vectors 
Description We are currently developing a tracing technique using LeGO vectors, combining three colours (RGB), allowing the multiple genetic modification of cell populations in vivo. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact The results obtained from the application of this technology to the study of the brain function are currently reviewed as an article. This methods has sparkled many collaborations since its implementation, leading to grant applications. 
 
Description Collaboration in the Wellcome Trust Neuroimmunology Consortium 
Organisation Wellcome Trust
Department Wellcome Trust Strategic Award
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Joined the Wellcome Trust Neuroimmunology Consortium under grant awarded to Prof Perry. Provided expertise in CSF1R targeting in Alzheimer's disease and general expertise in neuroimmunology.
Collaborator Contribution Provide drug candidates to target neuroinflammation in Alzheimer's disease.
Impact N/A
Start Year 2015
 
Description Identification of novel chemical inhibitors of CSF1R activation 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution We have evaluated the in-vivo activity of different inhibitors of CSF1R activation, in relation to the control of microglial proliferation in an experimental model of prion disease
Collaborator Contribution Novartis (Basel) identifies potentially bioactive compounds and selects the best candidates to be tested in-vivo
Impact n/a
Start Year 2013
 
Description ARUK South Coast Network Conference 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact "Living with Dementia" Conference of the ARUK South Coast Network, showcasing 3 invited lectures on Dementia Research plus several "scientific Cafes" led by local research groups.
Year(s) Of Engagement Activity 2017
 
Description Living with dementia 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Activity organised by the ARUK South Coast Network, to gather research scientists together with general public, to explain the causes and research being undertaken in Alzheimer's disease in Southampton.
Year(s) Of Engagement Activity 2016
 
Description Participation in speed careers event at Barton Peveril, as STEM Ambassador 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact More than 80 pupils from 3 different schools attended the speed careers event, gaining good insight into what being a scientist means.

n/a
Year(s) Of Engagement Activity 2014
 
Description When art meets science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We had an audience of 28 adults, which engaged with the presentation and asked many questions, providing very good feedback.

n/a
Year(s) Of Engagement Activity 2014
URL http://www3.hants.gov.uk/hampshire-museums/willis-museum/willis-museum-eventdetails.htm?id=247685