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

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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.