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

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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.