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

我们的免疫反应通常是一种防御机制，以防止感染的传播及其相关的组织损伤。在大脑中，炎症是一把双刃剑，由主要的常驻巨噬细胞群体小胶质细胞介导，其通过数量增加和激活炎症介质的产生来对疾病的发作作出反应，具有有益和有害的影响。然而，众所周知，在患有大脑退行性疾病的人中，如阿尔茨海默病（AD），炎症可能会加速疾病进展并加剧症状。当AD表现为明显的临床病理学时，小胶质细胞具有有害的贡献，产生可以干扰神经元之间的信号传导甚至影响其存活的炎症分子。然而，我们并不完全了解这个过程是如何发展的，以及小胶质细胞反应如何从疾病早期的反应发展到晚期的组织损伤。我们打算调查和了解的基本机制，调节AD的小胶质细胞的数量和激活。反过来，这可能会导致对这些疾病的保护或治疗方法的发展。在慢性神经退行性疾病的动物模型中，我们以前已经表明，针对越来越多的小胶质细胞是一个有前途的临床前干预。我们现在想了解小胶质细胞数量增加与我们看到的组织损伤之间的联系。在这个项目中，我们将揭示小胶质细胞如何从AD发病到后期慢性进展阶段调节它们的数量，以及这如何与从有益到有害的进展相关。我们假设，作为对早期病理学的反应，小胶质细胞增加了它们的增殖，但也增加了它们的死亡，加速了在健康大脑中维持这些细胞的自然周转机制。使用两种模拟AD样病理学的小鼠模型，我们将定义驱动AD中小胶质细胞数量随时间变化的速率和机制。我们将把小胶质细胞增殖的时间进展与从组织保护到组织损伤的转变的开始相关联，这是由于过多的周转周期而释放的。这将使我们能够确定小胶质细胞有害作用的开始时间，并确定这种转变的关键分子决定因素。我们将利用诱导型AD样病理的小鼠模型;我们会干扰小胶质细胞周转的驱动因素（增殖和死亡），确定所观察到的小胶质细胞周转失调的功能后果，其中包括组织损伤性炎症特征。这里提出的研究目标是一种新颖而雄心勃勃的方法来了解神经退行性疾病中的炎症，并将为神经免疫学和医学科学以及制药界提供重要信息。神经退行性疾病中小胶质细胞生物学的知识对于开发控制有害炎症反应的潜在治疗方法至关重要。众所周知，临床AD的发展之前是数年甚至数十年的亚阈值、进行性、病理学改变。通过所提出的方法，我们将为理解AD病理学的这些初始事件开辟新的领域，不仅可以理解生理学的早期变化，还可以设计潜在的干预措施来改变或阻止疾病的发展或进展。拟议研究的潜在成果将迅速转化为神经病理学诊所，并将改善这种疾病患者的生活质量。

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.