Defining neural circuit mechanisms for disorientation in preclinical Alzheimer's disease

Imagine going for a walk to the shop, but you get lost along the way. How do you find out where you are? One approach is to look for familiar clues, such as certain buildings or street signs, which will point you in the right direction. Another approach is to retrace your steps until you feel confident of the correct turn you need to make.

There are specialised neural pathways in the brain that provide us with a sense of direction. If these pathways are disrupted, they might cause disorientation, affecting one's ability to navigate. In fact, one of the earliest signs of dementia is disorientation, but it is not clear what mechanisms in the brain lead to this symptom.

If we can find out more about the neural pathways that lead to disorientation, we will be able to design better tests and treatments for dementia at earlier stages - when intervention is likely to have a bigger impact.

Alzheimer's disease - the most common form of dementia - is related to early changes in parts of the cerebral cortex that are important for episodic (event-based) memory. These neural pathways are affected by Tau, a key protein linked to Alzheimer's disease. Tau proteins change their shape and gradually build up to high levels inside nerve cells, which may affect their activity and disrupt communication, both within and between brain areas.

Another brain area known as the thalamus (located underneath the cortex) also contains Tau, even in people without dementia. The most vulnerable part of the thalamus contains specialised nerve cells that act like a compass, known as head direction cells. Could an early build-up of Tau in head direction cells explain disorientation?

In this project, we will first examine the neural pathways that are the most vulnerable to Tau at very early disease stages (preclinical Alzheimer's disease), focusing on head direction cell pathways between the thalamus and cerebral cortex. We will examine specially preserved brain samples from people that kindly donated their brains to Brain Banks, focusing on preclinical disease stages.

We will test whether Tau builds up within the nerve endings of head direction cells, which might explain how Tau spreads in the brain.

Next, we will test how the build-up of Tau within these specific neural pathways relates to disorientation by delivering human Tau to head direction cells in adult mice, which have very similar neural pathways to humans. We will test mice in specially designed mazes to see if they become disoriented and look for changes in the navigation strategies that they use. Then we will record from head direction cells in these mice to see how the activity of these cells is affected by human Tau.

Results of this project will inform us about how head direction cell pathways in the brain are affected by Tau, which may explain disorientation. The examination of human brain tissue alongside the mouse model will lead to new ways of detecting early signs of dementia in relation to the way people navigate, which could lead to more targeted and effective treatments.