Role of Wnt in the decline of oligodendrocyte generation in the ageing brain

The massive computing power of the brain depends on the insulation of nerve cell connections with myelin sheaths, by cells known as oligodendrocytes (OLs). Bundles of these 'myelinated' connections form the white matter that is very prominent in the human cortex. Although a loss of cortical white matter and myelin has been documented in cognitive decline, the causes are unknown.

There is evidence that OLs are continuously lost and regenerated from a pool of OL progenitors (OPs). For unknown reasons, the ability of OPs to generate OLs declines with age, which underlies the loss of myelin and cognitive functions. The applicant has identified a key factor that drives OL generation in the adult brain and which is deregulated in ageing. This factor is known as Wnt (pronounced wint), and the aim of this project is to determine the mechanisms by which Wnt controls OP generation and OL/myelin loss in the ageing mouse brain. This will provide new knowledge on the mechanisms underlying myelin loss in ageing brain and may ultimately lead to the identification of new cellular targets for protecting myelin and preserving cognitive function.

This fundamental research fits the BBSRC Research Priority of 'Healthy ageing across the lifecourse'.

Oligodendrocytes are specialised to form myelin in the CNS. Myelin is essential for rapid neuronal connectivity that underlies the massive computing power of the human brain. Studies in humans have shown loss of myelin and white matter shrinkage after the age of 50 is associated with decline of higher cognitive functions. Fate-mapping studies in mice provide direct evidence that this is normally replaced by oligodendrocytes newly generated from endogenous oligodendrocyte precursors (OPs). However, for unknown reasons there is a decrease in the regenerative capacity of OPs in the ageing brain. The mechanisms regulating oligodendrogliogenesis in the adult and aging brain are unresolved. However, the applicant provides several new lines of evidence of a fundamental role for deregulation of Wnt signalling. In recent studies, the applicant has identified a major role for Wnt in driving oligodendrogliogenesis and myelination in vivo in the mouse brain (Azim et al., 2014a,b). Now, in pilot studies on the optic nerve, an archetypal CNS white matter tract, we show that Wnt signalling continues to drive oligodendrogliogenesis in the mature adult nerve but not in old-age (18 months, equivalent to age 60 in humans). Furthermore, we show that multiple elements of Wnt signalling that control oligodendrocyte generation are severely altered in ageing white matter. To take this work forward, the applicant has developed a Cre/LoxP mouse line that targets Wnt signalling in OPs. These mice provide a major new advance that will enable the applicant to achieve the aims of this project and test the hypothesis that deregulation of Wnt signalling underlies the decreased regenerative capacity of OPs in the ageing brain. The planned epxeriments will generate new fundamental knowledge on the functions of Wnt in oligodendrocyte cell biology and mechanisms of cognitive decline in the ageing brain.

The main beneficiaries of the research will be other scientists, and dissemination of research findings will be through the normal routes of publications, reviews and presentations at meetings. In the longer term, this research is also likely to be of interest to clinicians, patient groups, and the wider public. We will publicise the support we receive for this project and explain the research through public forums. Where possible, we will make ourselves available to speak to local and national media on the importance of this research to the public and how grant support drives this much needed fundamental research.
It is not anticipated that any directly patentable data will arise from this project, but the longer term plan is to use the information gained in this research to identify new potential therapeutic targets for promoting a healthy brain in ageing and across the lifecourse. This would have considerable wider impact. We will use several routes to communicate this to potential user groups and the general public. We will present live demonstrations to local schools and the public, and write articles for specialised magazines for patients who may benefit from the findings of this research project. In addition, this project is directly relevant to ageing research and as a member of the University of Portsmouth Ageing Network (UPAN) and Alzheimer's Research UK (ARUK) Southern Network co-ordinated out of Southampton University, the applicant will have a direct route to communicate this research to potential end-users and interst groups.