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

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.

Cognitive decline with ageing is linked to loss of integrity of myelin, the insulation surrounding nerve fibres in the central nervous system (CNS) which is required for neuronal function. Mechanisms controlling myelin integrity in ageing are unknown, yet CNS macrophages termed microglia are known to regulate myelin integrity in youth, and are dysregulated in ageing. Thus, I propose that microglia dysregulation in ageing contributes to loss of myelin integrity and cognitive decline. Aim1 is to determine how aged microglia are dysregulated in association with loss of myelin integrity. We will determine how communication between microglia and cells that make myelin (termed oligodendrocytes) is altered in ageing via transcriptomics. In human brain, transcriptomic changes at the single-cell level on intact brain tissue will be correlated with myelin integrity and cognition in the same individual. In mouse brain, RNAseq will compare aged microglia and oligodendrocytes to young cells, narrowing down pathways related to myelin integrity by comparison to genetically altered mice in which microglia manipulation leads to premature loss of myelin integrity. Aim2 is to determine how aged microglia influence myelin integrity, by transplanting them into microglia-deficient mice or young wildtype mice, and assessing whether myelin integrity is disrupted. Aim3 is to determine whether rejuvenation of microglia improves myelin integrity and cognitive performance in ageing. First, we will use an approach known to rejuvenate microglia transcriptomes and improve cognition in aged mice: depletion of microglia followed by repopulation. Second, we will transgenically engage a pathway in microglia that is downregulated with ageing and involved in regulating myelin integrity and cognition: Wnt. We will supplement this with manipulation of pathways identified in Aim1, and assess whether myelin integrity and cognitive function are improved.