Research at the University of Southampton
A number of researchers at the University of Southampton are interested in understanding the mechanisms and processes behind the changes in the brain that occur during Alzheimer's disease. This research could pave the way for therapeutic interventions to prevent or delay the onset of irreversible damage that occurs in the brains of AD patients.
Dr Amrit Mudher
An exciting project led by Dr Amrit Mudher (Lecturer in Neuroscience), aims to investigate the cellular and molecular mechanisms by which the abnormal proteins implicated in neurodegenerative conditions such as AD disturb neuronal function. http://www.southampton.ac.uk/biosci/about/staff/amrit.page
Studies on brains of people who have died of Alzheimer's disease have shown us that the symptoms of dementia probably arise as a result of the presence of abnormal proteins in brain regions that control memory. These abnormal proteins lead to the formation of pathological hallmarks of disease.
In Alzheimer's disease there are two types of such pathological hallmarks: neurofibrillary tangles and neuritic plaques. The presence of both these hallmarks somehow cause the brain cells (neurons) to become "sick" and ultimately to die.
Neurofibrillary tangles are made up of a protein called tau. Normally tau protein is found in the longest part of a brain cell called an axon, where it binds to other proteins called microtubules and forms the cell skeleton (cytoskeleton). The cytoskeleton is very important for supporting the shape of the cell and for providing the tracks over which materials can be transported from one part of the cell to another (axonal transport). Brain cells rely on such transport of materials in order to communicate with each other.
In Alzheimer's disease the tau protein is abnormal, and many scientists believe that in this state, it cannot do its job properly. When this happens one would predict that the clinical function (such as memory and learning) that these affected nerve cells control becomes impaired (and it is then that the clinical symptoms of dementia - such as memory loss - emerge). This idea has been called the tau and tangle hypothesis.
This hypothesis had been proposed over ten years ago but it was not possible to test it using the available experimental tools. Using a fruit fly model of Alzheimer's Disease in which the fruit flies make large quantities of abnormal tau proteins (similar to the ones found in Alzheimer's Disease brains) in their nerve cells, we were able to understand how the abnormal tau proteins affected these nerve cells. We found that, as predicted by the tau and tangle hypothesis, abnormal tau proteins are indeed not able to do their job properly. They cannot form a proper cytoskeleton in the axon so there are very few tracks over which axonal transport can occur so it becomes impaired in the nerve cells of these fruit flies. These results demonstrated, for the first time, that abnormal tau proteins make nerve cells "sick" by disrupting the transport of valuable materials within the nerve cell. This disruption may be why the nerve cells cannot communicate with each other in Alzheimer's disease. The sick nerve cells in turn impact on the behavior of the flies. The fly larvae making abnormal tau protein can no longer crawl and navigate as well as normal larvae. Adult flies making abnormal tau protein are unable to climb effectively and they also die much earlier than normal flies.
We have used this fruit fly model to gain a better understanding of how the cytoskeleton breaks down as a result of abnormal tau being present. We have recently shown that the broken cytoskeleton can indeed be chemically put back together so that transport of materials can be resumed. We used a small compound called NAP (davunetide) to ‘sellotape' the cytoskeleton back together. This effectively prevented all of the ‘bad' effects of the abnormal tau protein and made the flies ‘well' again (Quraishe et al., 2013, Molecular Psychiatry).
Such research is important to pave the way for the design and development of similar drugs/compounds that work by this mechanism to treat Alzheimer's disease.
Dr Delphine Boche
Another exciting project led by Dr. Delphine Boche (Senior Lecturer in Clinical Neuroscience), aims to investigate the importance and contribution of inflammation in the brain in AD patients.
When we have an infection such as a cold or the flu, we feel sick, depressed, are not interested in things and generally are unable to concentrate. This is known as "sickness behaviour" and is the result of the brain not functioning well. In a healthy brain, this effect is reversible as we recover from the infection. However, we have reasons to think that, in someone who has Alzheimer's disease; this harmful effect on brain function is not reversible, but permanent.
The first response of the body to an infection is made by the macrophage - a cell of the immune system which is present everywhere in the body, including the brain. The presence of bacteria or viruses turns on the macrophages to produce chemicals that stimulate more macrophages and encourage them to kill the invaders. This process is known as inflammation.
Studies in laboratory animals have shown that the "sickness behaviour" effect occurs because macrophages in the brain have been switched on by the inflammatory chemicals produced following the infection in the blood.
In addition, animal studies have also shown that the "sickness behaviour" effect can be irreversible and permanent if brain cell damage, similar to Alzheimer's disease, has begun in the brain.
In Alzheimer's disease, the brain macrophages are switched on by the damage occurring in the brain (brain inflammation). Brain inflammation is now recognized as an important factor in the disease. Brain scans in people suffering from Alzheimer's disease show that inflammation is associated with greater deterioration in mental function.
The major genetic risk factor for Alzheimer's disease is possession of a version of the APOE gene called e4. Studies in laboratory animal and in human brain tissue have shown that with the e4 version, the activation of brain macrophages is greater following any sort of infection. This may explain, at least in part, why people with e4 are at greater risk of developing Alzheimer's disease.
In animal models of dementia, it has been shown that infection modifies the brain macrophages, which are already activated by the disease, so they become more aggressive adding to the damage to the brain. A study of infections in people with Alzheimer's disease, performed in Southampton, supports the idea that infection irreversibly accelerates the deterioration in mental function that is associated with Alzheimer's disease.
Our hypothesis is that common infections, such as a chest infection or a urinary infection, cause an increase in the brain damage in people with Alzheimer's disease. It is important to fully understand this because, if it is confirmed, it indicates that such infections in the elderly should be treated rapidly so as to protect the brain from further damage.
Changing Minds through Neuroscience Inspired Fashion
A collaboration between Winchester School of Art (WSA) and the Southampton Neuroscience Group (SoNG) was established with an aim to address the stigma and misconceptions surrounding mental health.
Each year the starting point for the project is a visit from SoNG members to Winchester School of Art to talk about our research which spans synaptic function, neurodegeneration and cognitive neuroscience. The importance of this basic research to neurological and psychiatric conditions is discussed and then some suggestions are made for topics that the students might like to consider as the design concept for their garment. A very important aspect of the project is that the design is carefully thought through in terms of the underlying neurobiology and the impact of the disease. To help with this the students visit the research labs and have the chance to discuss their ideas further with SoNG postdoctoral fellows and postgraduates.
This project has provided a stimulating, engaging and creative way to engage in conversations about mental health issues.
Designer: Vanessa Nogueira
"For this garment I felt it was important to capture the journey of a person suffering from Alzheimer's disease. It is the portrait of a mind filled with passion, ideas, creativity and life, and the slow dissolution of this."
Designer: Chloe Ride
"My project describes the emotion and experiences a person suffering from Alzheimer's may be feeling, not only for the person suffering from the disease but what their loved ones may be experiencing also. My main inspiration is an artist William Utermohlen, he suffered from the disease and recorded his experiences through self-portraits. My garment has a number of openings and can be worn several ways, signifying the confusion of the arrangement and order or clothing. A hand is trapped representing the isolation a sufferer may be experiencing and a pocket that doubles as an opening but completely coverers the wearers head, making the wearer disorientated and trapped within the vast amount of fabric consuming them."
Supported by the University of Southampton Multidisciplinary Research Strategy http://www.southampton.ac.uk/research/usrg/