Vulnerability of long-range axons in tauopathy

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Dementia, including Alzheimer's disease, is already one of most devastating illnesses and will get more common over the next few decades. Right now there are no treatments that can stop the disease progressing. The main symptoms of dementia involve the collapse of thinking skills like memory and problem-solving. The loss of these thinking skills is caused by the breakdown of communication within the brain. These skills require the careful coordination of activity in different parts of the brain. This communication between different brain areas is one of the first things affected as the disease takes hold. In this proposal, we aim to show why this long-range communication between different brain regions is selectively disrupted and to use this information to develop new treatments that target these early phases of dementia. Communication between different parts of the brain relies on signals passing between nerve cells, or neurons. To allow a neuron in one brain area to directly communicate with a neuron in another part of the brain, it has a very long protrusion, called its axon, which extends out away from neuron's home location into different brain areas. This axon may have to extend very long distances within the brain, even passing right over to the other side to reach its target area. The idea underlying this proposal is that it is these long axons that are vulnerable to damage in the early stages of dementia. Because these axons are so long, the neurons face a very tricky problem of how to get all the necessary nutrients down all the way to the end of the axons. One of the key things that neurons must transport down their axon are mitochondria, which supply the cell's energy. They provide the energy for the axons to stay healthy and to power communication with its target neurons. These mitochondria are transported like little mobile power stations down long tracks inside the axon. In our latest experiments, we have seen that if neurons are in an early stage of dementia, their mitochondria simply cannot travel down these train tracks as well as they do normally. We believe that this could present serious problems for the energy demands at the end of a long axon and maybe why these particularly long axons find themselves vulnerable to the effects of dementia. In the study, we will link this broken mitochondrial transport to the damage that is done to axons during dementia. If our idea is correct, when we image axons far away from their home area, we are more likely to see signs of sickness before we see it in axons that are close to home. To relate this back to the poor coordination of brain activity seen in dementia patients, we will check for impaired communication between those long axons with their target neurons. If these long-range axons are getting sick because of their transport problems, we can use that knowledge to treat them. As such, we will test if drugs that speed up transport of mitochondria in axons can protect long-range axons from getting sick. This will provide the proof-of-concept for development of new treatments for dementia.In this project, it is crucial that we see the axons as they are in the brain, with their complex shapes that determine which brain areas they connect with. This presents challenges because axons and their mitochondria are tiny, and they are buried deep inside the brain. To overcome these challenges, we will use a collection of cutting-edge imaging techniques. The first of these uses powerful lasers that can image deep inside the living brain without damaging it. The second approach uses special chemical treatments to make the brain transparent, like glass, so we can image through it, revealing the axons inside. The third approach uses another chemical trick to help us see the tiny mitochondria - by infusing an expanding gel into the brain we can make them bigger. This will allow us to see far greater detail about the inner workings of axons than previously possible.