Alzheimer’s affects around 496,000 people in the UK yet, so far, no single cause has been identified. There are drugs available to treat it, but there is no cure. Aston stem-cell biologist, Dr Eric Hill, is interested in creating a dynamic model of Alzheimer’s which moves the field away from animal research or the use of brain banks, using, instead, new developments in stem-cell technology to create what he terms a “disease in a dish”.
Alzheimer’s is the most common cause of dementia, yet the complexity of the human brain makes it a challenging disease to understand. The effects are devastating: loss of memory, mood changes and problems with communication and reasoning. Not a great deal is known about its causes. In less than five percent of the population, genetic elements are involved, though for the majority of Alzheimer’s sufferers, the disease appears to be quite sporadic.
Fighting an Unknown Enemy
Dr Eric Hill, who is based in Aston’s Research Centre for Healthy Ageing, agrees that there is still a lot to understand about the role that certain proteins play in the brain, and what might cause them to malfunction.
“Even some of the genes involved in Alzheimer’s, like the Amyloid precursor protein, we don’t really know what their normal function is in the brain, so we don’t know how they contribute to a disease,” he explains. “There are lots of things that the animal models have solved to date - how these genes, if you over-express them, can cause Alzheimer’s - but we still don’t fully understand the initial reasons why those genes can go wrong in patients with sporadic forms of the disease.”
One of the common approaches to understanding Alzheimer’s has been to examine tissue from a brain bank. However, as Dr Hill explains, the method has its drawbacks.
“You can look at the pathology of the disease and how the brain looked when the person died,” he says, “but you don’t know how those steps came into play. We think that Alzheimer’s could actually have started a long time before you actually start to develop overt symptoms. It’s a really difficult scenario because if you’re developing a blood test for Alzheimer’s, when would you test and who would you test? If you’re developing a new drug for Alzheimer’s, when would you start giving it to people if you don’t know for certain when they’re going to develop it?”
Towards a Better Model
While there have been useful drug developments for sufferers of Alzheimer’s, Dr Hill believes that the absence of an effective model may explain why scientists have yet to come up with a cure - or even a robust treatment. His aim is to create a more accurate picture of the disease by using stem cells.
“We decided that we wanted to work with things that look like proper brain cells,” he says. “Although there are a lot of cancer cell lines that you can use, they just keep dividing, and we know that your brain doesn’t do that. So we felt that using stem cells and turning them into brain cells that no longer divide would be a good starting point.”
Dr Hill is using induced pluripotent stem cell technology - a relatively new technique pioneered by Shinya Yamanaka’s lab in Kyoto, Japan, in 2006. Skin cells are taken from an Alzheimer’s patient and reprogrammed in the lab to become stem cells. The stem cells are then turned into brain cells which may develop Alzheimer’s-type symptoms. The advantage of this approach is that the disease can be observed in the context of an individual’s genome.
“If the skin cells were taken from a patient who has a form of Alzheimer’s associated with a particular gene, you can see if the disease still develops in the dish,” says Dr Hill. “A number of iPSC cells carrying mutations have now been looked at, and the cells do seem to develop certain things that are associated with the disease, like some proteins that are misfolded and start to aggregate together. So I think these are exciting new models that we can start to use to give us a better reflection of what’s actually going on in particular patients.”
Building a 3D Brain
Plenty of work still lies ahead in this field, but the hope is that even more accurate models might become viable. Instead of growing cells in two dimensions, for example, it might be possible to create a 3D model of the brain which replicates millions of neurons connected to each other. Yet, increasingly, challenges like these rely on interdisciplinary approaches - and on funding.
“I think that catching Alzheimer’s early and developing drugs that stop it spreading is probably a very good idea,” adds Dr Hill. “It’s quite interesting that things like a good diet and exercise can slow down Alzheimer’s, which leads us to wonder if there are some environmental causes. If you consider one aspect of the disease, such as the changes in glucose uptake in the brains of Alzheimer’s patients, could we get people doing more exercise and being healthier in order to rectify this situation? However, the disease is far more complicated than that, and there are many different angles that you could use to tackle it. I think we’re probably quite far away - probably ten years or more - from developing any kind of drugs, but people are doing some really good work, and it needs to continue.”