Cholesterol esters of oligodendrocytes in developmental and ageing brain

点击翻译按钮获取中文摘要

Our world now has a big ageing population with more than 900 million people aged 60 and over living on the planet, and this number is set to double reaching 2 billion by 2050. This is one of the biggest challenges facing our time since cases of age-related diseases will be rising, placing a heavy burden on the health care systems of all affected countries including the UK. Ageing can cause a gradual decline in cognitive capacity, often manifested as forgetfulness and decreased problem solving ability in people of old age, and progressive cognitive decline is an ominous sign of developing dementia and Alzheimer's disease (AD) - the most common neurodegenerative disorder. To find the cause of age-related cognitive decline, we first need to understand what happens in our brain in ageing.Brain is composed of different types of neurons and glial cells. Neurons are the function units in the brain; they communicate with each other through synapses and network together into circuits that process specific information and control particular biological functions. Glial cells provide support and protection for neurons and, importantly, form "myelin", the fatty insulating sheath enwrapping nerve fibres. Myelin enables extremely rapid propagation of nerve impulses, substantiating rapid and fine control of movement and high-speed brain computation. Age-related alterations to myelin structure have been seen in the brain of old primates, resulting in myelin breakdown.Lipids account for 80% of myelin dry weight and among these lipids, cholesterol is thought able to drive myelin synthesis and provide stability for myelin sheaths. 70-90% of the brain cholesterol resides in myelin. Brain needs to synthesize cholesterol locally because there exists a barrier between our blood circulation and brain, which prevents materials including free cholesterol in the bloodstream from entering the brain. Excess brain cholesterol can be converted into cholesterol esters (CEs) by an enzyme, ACAT1, and stored as lipid droplets inside cells. Increasing research findings have linked CE accumulation to age-related neurodegenerative diseases such as AD.In the brain, myelin is supplied by oligodendrocytes (OLs). OLs are generated from OL precursor cells (OPCs) through cell differentiation during OL development. Although OLs show remarkable longevity, OPCs can continue to proliferate and differentiate into OLs in adulthood, but these abilities decline with age. Our preliminary data show that ACAT1 is expressed in mouse OLs and OPCs, and we also discovered that ACAT1 expression along with the levels of certain CEs is markedly increased in old age in mouse brain tissues that are rich in myelin. Taken together, we hypothesize that CE accumulation in OLs may occur in ageing, impacting on OL function, myelin integrity and consequently on brain function. In this proposed study, we will analyse lipid composition of mouse myelin collected from the brain at different ages to identify myelin CEs and reveal how their levels change with age. We will also delete Acat1 specifically in mouse OPCs and/or OLs by genetic engineering to block cholesterol conversion into CEs in those cells; we will then collect brain tissues from these mutant mice at different OL development stages or at different old ages to examine the effect of lacking CEs on OL development or on OPC function, OL generation and myelin maintenance in ageing. In addition, we will feed mice of old age on a high cholesterol diet and find out the impact of high cholesterol intake on myelin cholesterol/ CE levels, OPCs, OLs and myelin structure in ageing.