Cholesterol esters of oligodendrocytes in developmental and ageing brain

我们的世界现在有一个庞大的老龄人口，超过9亿60岁及以上的人生活在地球上，到2050年，这个数字将翻一番，达到20亿。这是我们这个时代面临的最大挑战之一，因为与年龄有关的疾病病例将不断增加，给包括英国在内的所有受影响国家的医疗保健系统带来沉重负担。老龄化会导致认知能力逐渐下降，通常表现为老年人的健忘和解决问题能力下降，而渐进性认知能力下降是发展痴呆症和阿尔茨海默病（AD）的不祥征兆-最常见的神经退行性疾病。要找到与年龄相关的认知能力下降的原因，我们首先需要了解大脑在衰老过程中发生了什么。大脑由不同类型的神经元和神经胶质细胞组成。神经元是大脑中的功能单位，它们通过突触相互沟通，并通过网络连接成处理特定信息和控制特定生物功能的回路。神经胶质细胞为神经元提供支持和保护，重要的是，形成“髓磷脂”，包裹神经纤维的脂肪绝缘鞘。髓磷脂使神经冲动的传播极其迅速，使运动和高速大脑计算的快速和精细控制得以实现。在老年灵长类动物的大脑中发现了与胆固醇相关的髓鞘结构改变，导致髓鞘分解。脂质占髓鞘干重的80%，在这些脂质中，胆固醇被认为能够驱动髓鞘合成并为髓鞘提供稳定性。70-90%的脑胆固醇存在于髓磷脂中。大脑需要在局部合成胆固醇，因为我们的血液循环和大脑之间存在一个屏障，阻止血液中的游离胆固醇等物质进入大脑。过量的脑胆固醇可以通过酶ACAT 1转化为胆固醇酯（CE），并以脂滴的形式储存在细胞内。越来越多的研究发现，CE积累与年龄相关的神经退行性疾病，如AD。在大脑中，髓鞘是由少突胶质细胞（OL）。OL是由OL前体细胞（OPC）在OL发育过程中通过细胞分化产生的。虽然OLs显示出显着的寿命，OPCs可以继续增殖和分化成OLs在成年期，但这些能力随着年龄的增长而下降。我们的初步数据显示ACAT 1在小鼠OL和OPC中表达，并且我们还发现ACAT 1的表达沿着某些CE的水平在富含髓鞘的小鼠脑组织中的老年显著增加。综上所述，我们假设，CE在OL中的积累可能发生在衰老过程中，影响OL功能，髓鞘完整性，从而影响脑功能。在这项拟议的研究中，我们将分析从不同年龄的大脑中收集的小鼠髓鞘的脂质组成，以识别髓鞘CE并揭示其水平如何随年龄变化。我们还将通过基因工程删除小鼠OPCs和/或OL中的Acat 1，以阻止这些细胞中胆固醇转化为CE;然后我们将收集这些突变小鼠在不同OL发育阶段或不同年龄的脑组织，以检查缺乏CE对OL发育或OPC功能的影响，OL生成和老化中的髓鞘维持。此外，我们将以高胆固醇饮食喂养老年小鼠，并了解高胆固醇摄入对髓鞘胆固醇/ CE水平、OPCs、OLs和老化过程中髓鞘结构的影响。

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.