Alzheimer’s disease: How ARMI Scientists are Working to Find New Treatments
Here at the Australian Regenerative Medicine Institute, we’re investigating the potential of regenerative medicine to treat, and hopefully, one day, reverse neurodegenerative diseases, such as Alzheimer’s.
Alzheimer’s disease is the most common cause of dementia, a condition that usually affects the brain as we get older. With approximately 305,000 Australians suffering from the disease, it’s very likely that each of us knows of a relative who lives with it. And with an increasingly ageing population, it’s predicted that this number will increase in the near future. There are huge concerns about what this means for our stressed healthcare system, which is why there is such a concerted effort to support brain research today.
Alzheimer’s disease is what is known as a neurodegenerative disease. That means the disease is caused by the death of brain cells, which leads to the shrinking of the brain. The death of brain cells results in a range of devastating symptoms, from confusion to problems with memory, to depression to the inability to control movement. Following diagnosis, people with Alzheimer’s disease typically have a life expectancy of three to ten years.
“Currently, there are no treatments that can do this [stop the progress of Alzheimer’s disease]; they are only able to temporarily improve symptoms. This is where our researchers come in.”
We know that patients with Alzheimer’s have tiny abnormal protein deposits that form in the brain, known as plaques and neurofibrillary tangles. These plaques and neurofibrillary tangles develop when sticky proteins start clumping together (i.e. aggregates). The plaques are made from a protein called beta-amyloid and these form outside dying brain cells. While neurofibrillary tangles are made from a protein called tau and these form inside brain cells.
But how do these protein aggregates and tangles cause brain cells to die? Overall, they disturb and have a negative impact on the delicate, sensitive and highly controlled environment of the brain. These aggregates are able to trigger a broad range of processes, both inside and outside brain cells, that are toxic. This includes interfering with vital cell signalling, protein production and transport, and the integrity of cell architecture, blocking important drainage systems of the brain or activating an inflammatory response. At first, the brain cells attempt to handle this problem by activating processes to help efficiently clear aggregating proteins or block them from forming. However, in a diseased ageing brain, systems that usually keep proteins in check deteriorate, become overwhelmed and are unable to prevent brain cell death triggered by the ensuing toxicities. It is this that drives neurodegeneration.
One of the problems with neurodegenerative diseases such, as Alzheimer’s, is that people live with the degenerative conditions well before symptoms surface. So when people are diagnosed with the disease, the damage done by such protein aggregates and tangles have been accumulating for a long time. This is why trying to prevent Alzheimer’s disease is such a difficult task. Because of this, a lot of research is focused on finding ways to try and stop the progress of or reverse the disease. Currently, there are no treatments that can do this; they are only able to improve symptoms temporarily. This is where our researchers come in.
At ARMI, the Nillegoda group is investigating a fundamentally important process in cell repair, which has the potential to efficiently untangle, or disaggregate these sticky and toxic protein aggregates and tangles. The underlying mechanisms of this novel process remain unexplored in neurodegeneration. Dr Nadinath Nillegoda, the head of the Nillegoda group, comes from a background of studying protein folding, misfolding, aggregation and disaggregation and is now applying this knowledge and expertise to neurodegenerative disorders such as Alzheimer’s disease and motor neuronal disorders.
“There are more than 20,000 proteins in our cells, and our body has a surveillance system that keeps everything in check. We have these guardian proteins generally known as molecular chaperones that act as monitors- they identify and largely correct mistakes that arise during the production and postproduction lifetime of proteins,” explained Nadinath. If mistakes cannot be corrected, these chaperones help target the misfolded or damaged protein for clearance. These surveillance systems deteriorate during ageing and contribute to the development of many neurodegenerative diseases.
In Nadinath’s previous work, he investigated a surveillance system that was able to breakdown existing protein aggregates and prevent new aggregates from forming. This activity was first discovered in simple organisms (in bacteria, yeast and plants). But the molecular machine performing aggregate solubilisation (i.e. pulling apart the protein aggregates) does not exist in more complex organisms, such as humans. However, in 2015, in a seminal publication in the journal Nature, led by Nadinath, it was found that another chaperone system was responsible for this activity in more complex, multicellular organisms. This discovery has since driven Nadinath’s research. “This involves the HSP70 chaperone system, configured with specific targeting factors called J-domain proteins and nucleotide exchange factors to form a machine that can bind to the surface of toxic protein aggregates and exert enough pulling force to break down and release the trapped proteins. The released proteins can be refolded and rescued or targeted for clearance,” said Nadinath.
If this system could be manipulated in the right way, it could be applied to clear the sticky, potentially toxic protein aggregates and tangles that form during certain neurodegenerative diseases and help neuronal cell repair. This approach presents a novel way of tackling these diseases, and not just addressing the symptoms, as currently, limited treatments do. This could not only stop brain cells from dying, but it could also potentially reverse some damage. In addition, this chaperone system could play a role in treating a number of other conditions ranging from diabetes to cancer where protein misfolding and aggregation occur. However, before this happens, there is still much more to be learnt about this new and exciting “protein disaggregation” machine in human cells.
“This insight potentially has powerful implications on many protein conformational disorders including Alzheimer’s disease and the way we treat it.” – Dr Nadinath Nillegoda
Currently, the Nillegoda group at ARMI is working hard to understand how this machinery is regulated, how it targets specific proteins to break down and exactly how this will affect brain cells in neurodegenerative diseases. This involves using model organisms of Alzheimer’s disease and other motor neuron disorders and testing what happens when this chaperone system is manipulated. “This insight potentially has powerful implications on many protein conformational disorders including Alzheimer’s disease and the way we treat it. I’m excited to explore the potential of this machinery, which could lead to the development of therapeutic strategies in the future that may help slow down neurodegeneration and improve the lives of people affected by these debilitating conditions,” said Nadinath.
The Nillegoda group is on the lookout for talented young scientists at MSc, PhD and postdoctoral level to join and develop these exciting new strategies to counteract neurodegeneration. Click here to find out more.
Support ARMI’s goal to understand more about new potential ways to treat Alzheimer’s disease.