Rising to the Challenge: Understanding causes and consequences of neural overactivation in young adult APOE-e4 carriers

载脂蛋白（APO）是一个在所有细胞中具有重要功能的蛋白质家族。有两个主要亚型和几个类别和亚类，其中之一是APOE这种蛋白质在大脑中表达，在那里它在神经发生，可塑性和修复中发挥作用。APO-E引起了最多的关注，因为它的三种形式之一（APOE-e4）是晚发性阿尔茨海默病最重要的已知遗传风险因素。此外，健康的老年e4变异携带者在成年后的智力下降比非携带者更严重。有趣的是，最近在我的实验室和其他人的实验中，在年轻的成年e4携带者中发现了一个令人惊讶的发现，他们在需要精神集中的任务中比非携带者表现得更好。对这些年轻人进行的大脑扫描显示，他们的大脑与非携带者不同，在完成认知任务时，关键大脑区域的激活水平增加。比较年轻（18-28岁）和中年（45-55岁）的e4携带者，我们发现中年e4携带者的大脑活动与健康老年人（70岁以上）志愿者的大脑活动相似。这为我们提供了一个实验假设，在e4携带者的整个生命周期中观察到的矛盾效应。总之，我们认为e4携带者在成年早期表现出不寻常的大脑激活，这产生了两个后果。1.它对大脑中对精神活动很重要的区域施加了过度的代谢压力。它耗尽了与任务相关的区域的晚年补偿激活能力，并需要与年龄不相称的其他大脑区域的招募，以应对任务需求。在上一个BBSRC项目的基础上，我们建议研究暴露于一组特定心理挑战的年轻E4携带者的行为和大脑激活模式。这项提议的目的是确定年轻的成年e4携带者的大脑在应对认知挑战时何时以及为什么过度激活。我们将发现过度活跃是否仅限于特定的认知处理模式，它是否总是存在或对任务要求做出反应，以及重要的是，它是否具有足够的可塑性，使其能够在某些情况下“关闭”。此外，我们将测试大脑过度活动与与挑战和压力相关的大脑损伤物质释放之间的关系，从而将大脑活动直接与APOE的e4变体产生长期负面大脑变化的潜在机制联系起来。研究成果将是：1）更好地理解携带载脂蛋白E的e4变体的早期生活后果2）识别引起e4携带者大脑过度激活的认知操作，以及3）理解将过度活动与年轻成年人大脑中破坏性应激激素释放联系起来的机制。这些进步将直接为行为和认知策略和技术的发展提供信息，这些策略和技术可以推荐给e4携带者。我们提出这将减轻大脑过度激活的影响，从而提高老年人健康认知老化的前景。因此，这项工作直接关系到当前的优先事项“老龄化研究：终身健康和福祉”以及战略计划中的战略优先事项3，即“产生关于老龄化生物机制的新知识”，并提供“基础生物科学，以改善整个生命周期的健康和生活质量，减少对医疗和社会干预的需求”。

Apolipoproteins (APOs) form a diverse family of proteins with important functions in all cells. There are two major subtypes and several classes and sub-classes, one of which is APOE This protein is expressed in the brain, where it has a role in neurogenesis, plasticity and repair. APO-E has attracted most attention because one of its three forms (APOE-e4) is the single most important known genetic risk factor for late onset Alzheimer's disease. Also, healthy older carriers of the e4 variant suffer a steeper decline in intellectual ability in older adulthood than do non-carriers. Intriguingly, recent experiments in my laboratory and others establish the surprising finding in young adult e4 carriers that they can out perform non-carriers on tasks requiring mental concentration. Brain scans performed on these young adults revealed that their brains differed from non-carriers in showing increased levels of activation in key brain regions when completing cognitive tasks. Comparing e4 carriers at young (18-28 years) and mid (45-55 years) adulthood, we found that brain activity in mid-adult e4 carriers resembled that normally seen in healthy older (70+) volunteers. This provides us with an experimental hypothesis for the paradoxical effects observed in e4 carriers across the lifespan. In sum, we suggest that e4 carriers are manifesting unusual brain activations from early adulthood, and that this produces two consequences. 1. It places undue metabolic stress on regions of the brain important for mental activity, 2. It exhausts the capacity for later-life compensatory activations in task-relevant regions and necessitates age-inappropriate recruitment of other brain regions in order to respond to task demands. Building on the last BBSRC project, we propose to look at behaviour and brain activation patterns in young e4 carriers exposed to a particular set of psychological challenges. The aim of this proposal is to determine when, and why, young adult e4 carriers' brains overactivate in response to cognitive challenge. We will find out if the overactivity is limited to particular modes of cognitive processing, whether it is always present or reactive to task demands, and, importantly, whether it is plastic enough to enable it to be 'switched off' under certain circumstances. In addition, we will test the relationship between brain overactivity and the release of damaging brain substances associated with challenge and stress, thereby linking the brain activity directly to a potential mechanism through which the e4 variant of APOE exerts negative long term brain changes. Research outcomes will be: 1) an improved understanding of the early life consequences of carrying the e4 variant of APOE 2) the identification of cognitive operations that elicit brain overactivations in e4 carriers, and 3) an understanding of the mechanisms that link overactivity to release of damaging stress-hormones in the young adult brain. Together these advances will directly inform the development of behavioural and cognitive strategies and techniques which can be recommended to carriers of e4. This we propose would mitigate the effects of brain overactivation and thereby enhance the prospects for healthy cognitive ageing in older adulthood. As such, this work relates directly to the current priority "Ageing research: lifelong health and wellbeing" and to Strategic priority 3 in the Strategic plan, to "Generate new knowledge of the biological mechanisms of ageing" and deliver "fundamental bioscience for better health and improved quality of life across the lifecourse, reducing the need for medical and social intervention".