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

阿尔茨海默病（AD）的许多风险因素，如中风，血压改变和APOE 4，AD的主要遗传风险因素，与大脑血流量减少有关。这种血流量的减少可能通过降低大脑小区域的局部氧水平，促进β淀粉样蛋白的产生而引发AD，β淀粉样蛋白对神经元有毒。我们想知道是否是这种情况，因为这样的治疗可以通过增加脑血流量和脑氧水平来预防AD，减少疾病的发生。我们已经发现，表达人类APOE4的小鼠在一些但不是所有血管中显示出早期血流量减少，并且当附近的神经元活跃并需要更多能量时，这些血管不太能够扩张以增加血流量。这支持了这样的观点：APOE 4导致大脑早期无法向活跃的脑组织提供足够的能量，并且APOE 4大脑中的氧气水平可能在这些血管附近变得不足。现在，我们想测试这种血流量的减少是否会促进由这些血管供血的组织中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，大脑活动，血氧水平和淀粉样蛋白斑块。我们将首先确定哪些血管在APOE4小鼠中不能很好地工作，然后“打开”β淀粉样蛋白的产生，看看β淀粉样蛋白是否在这些功能障碍的血管周围比在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变化。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，降低大脑中的整体氧气水平，加速β淀粉样蛋白和神经元损伤的积累。在一个平行的实验中，我们将观察这些小鼠和其他小鼠的死后组织，以测试β淀粉样蛋白最初积聚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其积聚。我们将使用针对β淀粉样肽的抗体来做到这一点，β淀粉样肽是在低氧时以增加的水平存在的蛋白质，以及在细胞特定区域中发现的蛋白质。为了检查血管是否因为大脑已经消耗了较少的能量而不能很好地工作，我们还将测量大脑切片消耗氧气的速率，并跟踪APOE 4和β淀粉样蛋白对氧气的影响。我们预计，在AD早期受到影响的大脑区域将具有最低水平的氧气和血管功能，甚至在β淀粉样蛋白产生之前，比那些在AD后期受到影响的人更好。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，我们将比较疾病早期受影响的区域（海马和内嗅皮层）与疾病后期受影响的区域（视觉皮层）。这将使我们能够了解大脑氧合和血管功能的早期改变是否与这些大脑区域对损伤的敏感性增加有关。最后，我们将给小鼠一种药物，通过保护称为周细胞的小血管细胞来增加脑血流量，以测试它是否也可以防止β淀粉样蛋白积累和记忆障碍，看看增加脑血流量和氧合是否是预防AD的有效策略。这项工作将发现脑血流量的减少是否会引发阿尔茨海默病，以及防止这种血流量的减少是否可能是一种重要的治疗策略。

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.