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

小胶质细胞如何在健康和衰老过程中调节髓磷脂完整性和认知功能？

基本信息

批准号：
MR/V031260/1
负责人：
Veronique Miron
金额：
$ 280.09万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV031260%2F1
关键词：
How do microglia regulate myelin

项目摘要

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.

正常衰老的智力下降会导致日常生活的问题，但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层，称为髓磷脂。髓鞘结构的变化随着年龄的增长而发生，例如髓鞘解开或变得更厚，这些变化与衰老中的智力下降有关。确保髓鞘的适当结构可能是一种有前途的治疗方法，以改善老年人的智力。然而，目前还不清楚是什么控制髓鞘结构。我的实验室和其他人的工作揭示了一个控制髓鞘和智力结构的新角色：生活在大脑中的称为小胶质细胞的免疫细胞。我们发现，在人类和小鼠大脑中没有小胶质细胞的情况下，髓鞘结构的变化就像在衰老中看到的那样。这意味着髓鞘的正确结构需要小胶质细胞。由于我们知道小胶质细胞在衰老过程中不能正常发挥作用，这导致我提出，随着年龄的增长，小胶质细胞的变化会导致髓鞘结构的改变和智力下降。总体目标是了解小胶质细胞如何随着衰老而失去支持髓鞘结构的能力，以及我们如何针对这一点来改善衰老中的智力。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，来确定与不健康的髓鞘结构相关的衰老小胶质细胞的变化。我们将把这与制造髓鞘的细胞（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交流如何在衰老过程中发生变化。在人类中，我们将使用一个独特的大脑组织库，这些大脑组织来自老年人，他们的智力是在他们的一生中测量的。这将使我们能够使用一种新的方法来观察完整脑组织上单个细胞中的基因，将小胶质细胞、少突胶质细胞和髓鞘的变化与智力联系起来。我们将通过比较老年小鼠和年轻小鼠中小胶质细胞和少突胶质细胞的基因调控来补充小鼠的平行研究。我们将通过比较衰老细胞中的基因和基因改变的小鼠中的基因来缩小原因范围。在基因改变的小鼠中，操纵小胶质细胞会导致髓鞘结构的变化，这种变化也会在衰老中看到。第二个目标是了解小胶质细胞随着衰老的变化如何影响它们支持髓鞘结构的能力。为了确定老年小胶质细胞是否缺乏支持健康髓鞘结构的能力，我们将它们移植到没有小胶质细胞的小鼠体内，看看髓鞘是否适当地形成。为了确定老化的小胶质细胞是否会积极地使髓鞘不健康，我们将它们移植到年轻的小鼠体内，看看髓鞘结构是否发生了变化。第三个目标是测试操纵老化的小胶质细胞是否可以恢复髓鞘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点。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和重新填充。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/表现得像“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一种称为Wnt的信号分子的数量。Wnt信号在年轻的小胶质细胞中很活跃，但在老年时不太活跃。还可以测试从目标1中鉴定的其他途径。我们将测试这些老年小鼠的髓鞘完整性和智力是否在我们的干预后得到改善。因此，这项建议将衰老中的小胶质细胞和髓鞘问题与智力下降联系起来，并将确定治疗干预的新靶点。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging.

DOI：
10.1212/wnl.0000000000012997
发表时间：
2021-12-07
期刊：
Neurology
影响因子：
9.9
作者：
Conole ELS;Stevenson AJ;Muñoz Maniega S;Harris SE;Green C;Valdés Hernández MDC;Harris MA;Bastin ME;Wardlaw JM;Deary IJ;Miron VE;Whalley HC;Marioni RE;Cox SR
通讯作者：
Cox SR

Immuno-epigenetic signature derived in saliva associates with the encephalopathy of prematurity and perinatal inflammatory disorders

唾液中的免疫表观遗传特征与早产儿脑病和围产期炎症性疾病相关