Is Alzheimer's disease triggered by a failure of the brain's blood supply?

阿尔茨海默病是由大脑供血不足引发的吗？

• 批准号: MR/S026495/1
• 负责人: Catherine Hall
• 金额: $ 89.39万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS026495%2F1
• 关键词: Alzheimer; disease; triggered; failure; brain

Many risk factors for Alzheimer's disease (AD), such as stroke, altered blood pressure and APOE4, the main genetic risk factor for AD, are associated with a decrease in blood flow to the brain. This decrease in blood flow may trigger AD by reducing local oxygen levels in small regions of the brain, promoting production of beta amyloid, which is toxic to neurons. We want to find out whether this is the case, because then treatments could be targeted to protect against AD by increasing brain blood flow and brain oxygen levels, reducing the occurrence of the disease. We have already found that mice expressing human APOE4 show early decreases in blood flow in some, but not all, blood vessels, and these vessels are less able to dilate to increase blood flow when nearby neurons are active and require more energy. This supports the idea that APOE4 leads to an early failure of the brain to supply enough energy to active brain tissue, and that oxygen levels in APOE4 brains are likely to become inadequate near these vessels. Now, we want to test whether this decrease in blood flow promotes the build-up of beta amyloid in tissue fed by these vessels, leading to changes in neuronal activity and behaviour. We will test this by breeding mice that express APOE, and a form of beta amyloid that can be switched on and off, and a protein that tracks neuronal activity. In our first experiment, we will record blood vessel function, brain activity, blood oxygen levels, and amyloid plaques in these mice while they are alive. We will first identify which blood vessels don't work well in APOE4 mice, then "switch on" beta amyloid production to see if beta amyloid aggregates more around these dysfunctional blood vessels than around those where blood flow is normal, and whether the neuronal activity near these vessels changes as beta amyloid accumulates. Because beta amyloid itself impairs blood vessel function, we expect that the functioning of these blood vessels will become more and more impaired, decreasing overall oxygen levels in the brain and accelerating the build-up of beta amyloid and neuronal damage. In a parallel experiment, we will look at post mortem tissue from these and other mice, to test whether the regions where beta amyloid first builds up already have low oxygen levels, and which enzymes and organelles within the cell might be responsible for triggering its accumulation. We will do this using antibodies against beta amyloid peptides, proteins that exist at increased levels when oxygen is low and proteins that are found in specific compartments of the cell. To check that blood vessels don't work so well just because the brain is already using less energy, we will also measure the rate at which brain slices consume oxygen and track how this is affected by APOE4 and beta amyloid.We expect that the areas of the brain that are affected earlier in AD will have the lowest levels of oxygen and vascular function, even before beta amyloid is produced, than those that are affected later in AD. To test whether the sensitivity of some brain regions to AD is due to increased hypoxia in these areas, we will compare regions that are affected early in the disease (hippocampus and entorhinal cortex) with an area that is affected later in the disease (visual cortex). This will allow us to understand whether early alterations in brain oxygenation and vascular function are involved in the increased susceptibility of these brain regions to damage.Finally, we will give the mice a drug that increases brain blood flow by protecting small vascular cells, called pericytes, to test if it also prevents beta amyloid accumulation and memory impairments, to see if increasing brain blood flow and oxygenation could be a useful strategy to prevent AD. This work will discover whether a decrease in brain blood flow could trigger Alzheimer's disease and whether preventing this decrease in blood flow could be an important therapeutic strategy.

阿尔茨海默病(AD)的许多风险因素，如中风、血压变化和AD的主要遗传风险因素APOE4，都与流向大脑的血液减少有关。这种血流量的减少可能会通过降低大脑小区域的局部氧气水平，促进对神经元有毒的β淀粉样蛋白的产生，从而引发AD。我们想要找出是否是这样的情况，因为然后治疗可以有针对性地通过增加脑血流量和脑氧水平来预防AD，从而减少疾病的发生。我们已经发现，表达人APOE4的小鼠早期表现出一些(但不是所有)血管中血流量的减少，当附近的神经元活跃并需要更多能量时，这些血管扩张以增加血流量的能力较弱。这支持了这样一种观点，即APOE4导致大脑早期衰竭，无法为活跃的脑组织提供足够的能量，而且APOE4大脑中的氧气水平可能在这些血管附近变得不足。现在，我们想要测试血流量的减少是否促进了由这些血管供应的组织中β淀粉样蛋白的积累，从而导致神经元活动和行为的变化。我们将通过培育表达APOE的小鼠来测试这一点，APOE是一种可以打开和关闭的β淀粉样蛋白，以及一种跟踪神经元活动的蛋白质。在我们的第一个实验中，我们将记录这些小鼠活着时的血管功能、脑活动、血氧水平和淀粉样斑块。我们将首先确定APOE4小鼠中哪些血管工作不佳，然后“开启”β淀粉样蛋白的产生，看看这些功能障碍的血管周围的β淀粉样蛋白是否比血流正常的血管周围聚集得更多，以及这些血管附近的神经元活动是否随着β淀粉样蛋白的积累而改变。由于β淀粉样蛋白本身会损害血管功能，我们预计这些血管的功能将变得越来越受损，降低大脑中的总体氧气水平，并加速β淀粉样蛋白和神经元损伤的积累。在一项平行的实验中，我们将观察这些和其他小鼠的死后组织，以测试β淀粉样蛋白首先积累的区域是否已经具有低氧水平，以及细胞内的哪些酶和细胞器可能负责触发它的积累。我们将使用针对β淀粉样多肽的抗体来实现这一点，β淀粉样多肽是在低氧时存在的水平升高的蛋白质，以及在细胞的特定隔室中发现的蛋白质。为了检查血管不能很好地工作，仅仅是因为大脑已经在消耗更少的能量，我们还将测量脑片消耗氧气的速度，并跟踪APOE4和β淀粉样蛋白是如何影响这一点的。我们预计，在AD早期受到影响的大脑区域，甚至在β淀粉样蛋白产生之前，大脑的氧气和血管功能水平将比AD后期受到影响的区域更低。为了测试某些大脑区域对AD的敏感性是否是由于这些区域的缺氧增加所致，我们将比较疾病早期受影响的区域(海马体和内嗅皮层)和疾病后期受影响的区域(视觉皮质)。这将使我们能够了解大脑氧合和血管功能的早期变化是否与这些大脑区域对损伤的易感性增加有关。最后，我们将给小鼠一种通过保护称为周细胞的小血管细胞来增加脑血流的药物，以测试它是否也可以防止β淀粉样蛋白积聚和记忆障碍，看看增加脑血流量和充氧是否是预防AD的有效策略。这项工作将发现脑血流量减少是否会引发阿尔茨海默病，以及防止这种血流量减少是否可能是一种重要的治疗策略。

项目成果

Choice of method of place cell classification determines the population of cells identified

位置细胞分类方法的选择决定了所识别的细胞群

• DOI: 10.1101/2021.02.26.433025
• 发表时间: 2021
• 作者: Grijseels D

An open-source pipeline for analysing changes in microglial morphology.

• DOI: 10.1098/rsob.210045
• 发表时间: 2021-08
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Clarke D;Crombag HS;Hall CN
• 通讯作者: Hall CN

First, tau causes NO problem

首先，tau 不会造成任何问题

• DOI: 10.1038/s41593-020-0691-x
• 发表时间: 2020
• 期刊: Nature Neuroscience
• 影响因子: 25
• 作者: Bonnar O

The Emergence of a Stable Neuronal Ensemble from a Wider Pool of Activated Neurons in the Dorsal Medial Prefrontal Cortex during Appetitive Learning in Mice

• DOI: 10.1523/jneurosci.1496-19.2019
• 发表时间: 2020-01-08
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Brebner, Leonie S.;Ziminski, Joseph J.;Koya, Eisuke
• 通讯作者: Koya, Eisuke

Extinction of cue-evoked food-seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice.

线索诱发的食物寻求消失会在小鼠背内侧前额叶皮层中招募 GABA 能中间神经元群。

• DOI: 10.1111/ejn.14754
• 发表时间: 2020
• 期刊: The European journal of neuroscience
• 作者: Brebner LS