Is the microglial response in Alzheimer's disease determined by a dysfunctional balance of proliferation and survival?

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

Abstract

Our immune response is usually a defensive mechanism to prevent the spread of infections and their associated tissue damage. In the brain, inflammation is a double-edge sword mediated by the main resident macrophage population, the microglia, which reacts to the onset of disease by increasing in number and activating the production of inflammatory mediators, having both beneficial and detrimental effects. However, it is well known that in people with degenerative diseases of the brain, such as Alzheimer's disease (AD), inflammation may accelerate disease progression and exacerbate symptoms. When AD manifests as an overt clinical pathology, microglia have a detrimental contribution, generating inflammatory molecules that can interfere with signalling between neurons and even affecting their survival. However, we do not fully understand how this process develops, and how the microglial reaction progresses from its response at early stages of disease to its late tissue-damaging contribution. We intend to investigate and understand the fundamental mechanisms that regulate the number and activation of microglia in AD. In turn, this could lead to the development of protective or therapeutic approaches against these diseases.

In animal models of chronic neurodegeneration we have previously shown that targeting the increasing numbers of microglia is a promising pre-clinical intervention. We now want to understand the link between the increased microglial numbers with the tissue damage we see. In this project we will uncover how microglia regulate their numbers from the onset of AD to its later chronic progressive stage, and how this correlates with the progression from a beneficial to a detrimental contribution. We hypothesise that, in reaction to early-stage pathology, microglia increase their proliferation but also their death, accelerating the natural turnover machinery that maintains this cells in the healthy brain. Using two mouse models that mimic AD-like pathology, we will define the rates and mechanisms driving the change in microglial numbers over time in AD. We will correlate the temporal progression of microglial proliferation with the onset of the switch from a tissue-protecting to a tissue-damaging profile, unleashed as a consequence of an excessive number of turnover cycles. This will allow us to time the onset of the detrimental actions of microglia and pin down key molecular determinants of this transition. We will take advantage of a mouse model of inducible AD-like pathology; we will interfere with the drivers of microglial turnover (proliferation and death) from their onset, identifying the functional consequences of the observed dysregulation of microglial turnover, which would include a tissue-damaging inflammatory profile.

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 and pharmaceutical communities. The knowledge of microglial biology during neurodegenerative disease is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. It is well known that the development of clinical AD is preceded by years or even decades of sub-threshold, progressive, pathological alterations. With the proposed approach, we will break new ground into the understanding of those initial events of AD pathology, allowing not only the comprehension of the early changes in physiology but also the potential design of interventions to modify or arrest the disease development or progression. The potential outcomes of the proposed research would be rapidly translated into the neuropathology clinics, and would improve the quality of life of patients with this disease.

Technical Summary

We hypothesise that an accelerated microglial turnover in response to Abeta accumulation in AD is triggered at disease onset, driving replicative senescence in microglia and unleashing the detrimental inflammatory profile characteristic of AD. We will define the basic parameters regulating the number of microglia in a mouse model of AD-like pathology (APP/PS1), including the definition of the time-course of the rates of proliferation and apoptosis, and the cell cycle length, using pulse-chase studies coupled to flow cytometry (FC). We will then profile the transcriptome of microglia isolated at different stages of the pathology, in order to understand the correlation of any observed changes in microglial turnover with the alteration of the inflammatory profile. With these two sets of data, we will be able to predict the time when a microglial cell can develop replicative senescence, arising from the accumulation of an excessive number of cycling events. Then, we will use TetO-APPSweInd mice, which will allow to control the onset of Abeta pathology, in order to accurately define the sequence of linking the early onset of amyloidosis to delayed changes in the microglial inflammatory phenotype. We will then prevent the transition of microglia to a detrimental phenotype by interfering with microglial proliferation or apoptosis, as a mechanistic intervention to discover the functional contribution of these mechanisms to the observed pathological changes. Using TetO-APPSweInd mice will also allow switching off Abeta pathology, and downstream analysis of the reversibility of the observed changes in microglial turnover and phenotype. We will collaborate with relevant experts in key technical aspects of the proposal, allowing a comprehensive analysis of our hypothesis. These experiments will define the time course of the contribution of microglia to AD, allowing the understanding of the events developing in the brain years before the onset of AD's clinical manifestations.

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. Research into dementia is therefore of much interest and concern for society, the findings in this study would be of interest to the general public, but in particular to the community of AD patients, families and carers: the project will move the understanding of AD development and potentially identify future therapies for the disease. We are ambitious and hope to provide effective ways to tackle the progression of dementia, which in turn may have a beneficial impact on the daily life of dementia patients and providing novel therapeutic tools to the health system.
Our recent research has provided a solid background supporting the hypothesis that targeting neuroinflammation is a promising therapy in dementia, and we are currently progressing to this goal by collaborating with several industrial partners (Esai, Lilly, JNJ, GSK, Pfizer, Abbvie) under two public-private-initiatives (PPI). These aim at accelerating translation of research from bench to bed, and we are fully committed to continue following this model to translate our future findings. We will maintain a fluid communication with our key industrial links, to include them into the early development of collaborative projects, aiming at early target identification and/or target validation. This will be facilitated locally thanks to engagement with the Research Enterprise and Engagement Champions (REECh), a committee there to maximize enterprise, innovation, and outreach activities for staff based within Biological Sciences at UoS. We will also seek advice from Research and Innovation Services (RIS), who can help to identify IP and explore appropriate commercial strategies.
We are committed to skilling up next generation of academic researchers. We will provide the PDRA and RA with transferable skills of project management, research design and evaluation, supervision/mentoring of junior staff/students and public engagement training. PDRA's participation in appropriate events run by the University's Professional Development Unit will be encouraged and supported. PDRA will present at LifeLab/Science Day/Conferences as well, as part of our impact strategy.
We are also committed to bring the findings of our research to the general public. The team members will be involved in STEM activities at local schools, as well as communicate our findings to the public audience by using different platforms available at the University (Science day, Pint of Science, LifeLab), on a yearly basis. We will invite into the lab for a tour volunteers of the Alzheimer's Society and Alzheimer's Research UK to make them part of the research we are developing. As part of the ARUK South Coast Network, we will participate in engagement activities related to dissemination of research on dementia to the local public and to dementia patients and/or their relatives, including the annual network open day. This will potentiate the involvement of AD community in research activities, and will provide a valuable two-way flow of information to better frame our research.
Will maximize media coverage of our research findings. Significant outcomes will be presented publicly in a timely manner via the University of Southampton web sites, and approach that has served efficiently to maximise the reach of our research.

Publications

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Carroll L (2021) Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity. in The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

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Gomez-Nicola D (2019) Measuring Microglial Turnover in the Adult Brain. in Methods in molecular biology (Clifton, N.J.)

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Menassa DA (2018) Microglial Dynamics During Human Brain Development. in Frontiers in immunology

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Michelucci A (2018) Microglia in Health and Disease: A Unique Immune Cell Population. in Frontiers in immunology

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Morgan AR (2019) Inflammatory biomarkers in Alzheimer's disease plasma. in Alzheimer's & dementia : the journal of the Alzheimer's Association

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Obst J (2017) The Role of Microglia in Prion Diseases: A Paradigm of Functional Diversity. in Frontiers in aging neuroscience

 
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