How do microglia regulate myelin integrity and cognitive function in health and ageing?

随着年龄的增长，智力下降会导致日常生活出现问题，但目前还没有预防这种下降的治疗方法。正常的智力需要包裹在中枢神经系统神经纤维周围的绝缘物质，即髓磷脂。髓磷脂结构的变化随着年龄的增长而发生，例如髓磷脂分解或变厚，这些变化与衰老时智力下降有关。确保髓磷脂的适当结构可能是一种很有前途的治疗方法，可以提高老年人的智力。然而，是什么控制髓磷脂结构尚不清楚。我的实验室和其他人的研究揭示了一个控制髓磷脂和智力结构的新角色：一种叫做小胶质细胞的免疫细胞，它生活在大脑中。我们发现，在人类和小鼠大脑中缺乏小胶质细胞的情况下，髓磷脂结构的变化就像在衰老过程中看到的那样。这意味着髓磷脂的正常结构需要小胶质细胞。既然我们知道小胶质细胞在衰老过程中不能正常工作，这就导致了我的建议：随着年龄的增长，小胶质细胞的变化导致了髓鞘结构的改变和智力的下降。总体目标是了解小胶质细胞如何随着年龄的增长而失去支持髓磷脂结构的能力，以及我们如何针对这一点来提高智力。第一个目标是通过观察小胶质细胞基因是如何异常调节的，来确定与髓磷脂结构不健康相关的衰老小胶质细胞的变化。我们将把这种变化与制造髓磷脂的细胞（称为少突胶质细胞）的变化进行比较，以了解小胶质细胞和少突胶质细胞之间的通信在衰老过程中是如何变化的。在人类中，我们将使用一个独特的脑组织库，这些脑组织来自老年人，他们的智力是在一生中测量的。这将使我们能够使用一种新的方法来观察完整脑组织中单个细胞的基因，从而将小胶质细胞、少突胶质细胞和髓磷脂的变化与智力联系起来。我们将在小鼠中进行平行研究，通过比较老年小鼠和年轻小鼠小胶质细胞和少突胶质细胞的基因调控来补充这一研究。我们将通过将衰老细胞中的基因与基因改变小鼠中的基因进行比较来缩小原因，在基因改变小鼠中，对小胶质细胞的操纵会导致髓磷脂结构的变化，这种变化在衰老过程中也会出现。第二个目标是了解随着年龄的增长，小胶质细胞的变化如何影响它们支持髓鞘结构的能力。为了确定衰老的小胶质细胞是否缺乏支持健康髓磷脂结构的能力，我们将它们移植到没有小胶质细胞的小鼠体内，看看髓磷脂是否形成适当。为了确定年老的小胶质细胞是否主动使髓磷脂不健康，我们将它们移植到幼鼠体内，观察髓磷脂结构是否发生变化。第三个目标是测试操纵衰老的小胶质细胞变得“年轻”是否可以恢复髓磷脂的完整性并提高智力。我们将使用两种概念验证方法，通过操纵小胶质细胞和分子来实现这一目标。为了实现前者，我们将杀死大部分小胶质细胞，并允许剩余的小胶质细胞分裂并重新繁殖。我们从以前的工作中知道，这些新形成的小胶质细胞看起来像“年轻的”小胶质细胞。其次，我们将使用遗传方法来增加老年小鼠小胶质细胞中称为Wnt的信号分子的数量。Wnt信号在年轻的小胶质细胞中活跃，但在老年时不那么活跃。从Aim 1中确定的其他途径也可以进行测试。我们将测试这些老年小鼠的髓磷脂完整性和智力是否在我们的干预后得到改善。因此，这一建议将小胶质细胞和髓磷脂的问题与智力下降的衰老联系起来，并将确定治疗干预的新目标。

Decreased intellect with normal ageing can lead to problems with day-to-day living, yet there are no treatments that prevent this decline. Proper intellect requires the insulation which wraps around nerve fibres in the central nervous system, called myelin. Changes in the structure of myelin occur with ageing e.g. myelin unravels or becomes thicker, and these changes correlate with reduced intellect in ageing. Ensuring the proper structure of myelin could be a promising therapeutic approach to improve intellect in ageing. However, it is unclear what controls myelin structure. Work from my lab and others revealed a new player in controlling the structure of myelin and intellect: immune cells called microglia, which live in the brain. We show that in the absence of microglia in human and mouse brain, changes in myelin structure occur like those seen in ageing. This means that microglia are needed for the proper structure of myelin. Since we know microglia do not function properly in ageing, this leads to my proposal that changes in microglia with ageing contribute to altered myelin structure and intellectual decline. The overall aim is to understand how microglia lose their ability to support myelin structure with ageing, and how we can target this to improve intellect in ageing.The first objective is to identify the changes in ageing microglia that are associated with unhealthy myelin structure, by looking at how microglia genes are abnormally regulated. We will compare this to changes in cells that make myelin, called oligodendrocytes, to understand how the communication between microglia and oligodendrocytes changes in ageing. In humans, we will use a unique bank of brain tissue from aged individuals whose intellect was measured over their lifetime. This will allow us to use a new approach of looking at genes in individual cells on intact brain tissue to correlate changes in microglia, oligodendrocytes and myelin, to intellect. We will complement this with parallel studies in mice by comparing gene regulation in microglia and oligodendrocytes in aged mice to those in young mice. We will narrow down the causes by comparing genes in aged cells to those in genetically altered mice in which manipulation of microglia causes the changes in myelin structure which are also seen in ageing.The second objective is to understand how changes in microglia with ageing influences their ability to support myelin structure. To determine whether aged microglia lack the ability to support healthy myelin structure, we will transplant them into a mouse which doesn't have microglia and see if myelin is formed appropriately. To determine whether aged microglia actively make myelin unhealthy, we will transplant them into a young mice and see if myelin structure is changed. The third objective is to test whether manipulating aged microglia to become 'younger' can restore myelin integrity and improve intellect. We will do this using two proof-of-concept approaches, by manipulating microglia cells and molecules. To achieve the former, we will kill off a large proportion of the microglia and allow the remaining microglia to divide and re-populate. We know from previous work that these newly formed microglia appear like/behave like 'younger' microglia. Second, we will use genetic methods to increase the amount of a signalling molecule called Wnt in the microglia of aged mice. Wnt signalling is active in young microglia, but less active in old age. Additional pathways identified from Aim 1 can also be tested. We will test whether myelin integrity and intellect in these aged mice is improved following our interventions.This proposal thus links problems with microglia and myelin in ageing with decreased intellect, and will identify new targets for therapeutic intervention.