"Compound 10" is how Ursula Quitterer refers to the chemical compound that her team has developed and which could slow down the progression of Alzheimer's disease. Quitterer is Professor of Molecular Pharmacology at ETH Zurich and has so far tested the active ingredient first on mice, revealing promising effects: the typical death of nerve cells seen in dementia is significantly slower, and the animals survive for longer.
The new substance is the result of research that began almost 20 years ago, when Quitterer received tissue samples from patients of a doctor and colleague at the Ain Shams University Hospital in Cairo. These were samples of brain tissue that the doctor had removed during tumour surgery – both on people diagnosed with dementia and non-dementia patients.
New point of attack for drug
Quitterer set about working on these samples – but to understand what exactly she did with them, we first need a bit of background. Then, as now, the main focus of her research was a bodily enzyme that performs a vital role in many human cells: GRK2. As a regulatory protein, this enzyme helps cells respond correctly to signals, stress and strain. As well as in the heart, for example, it is also active in the brain – where it supports the function of nerve cells.
Through molecular analyses of the tissue samples from Cairo and research on mice, Quitterer's team showed what an important role the enzyme GRK2 plays in dementia. The researchers recently published their findings in the journal Cell Reports Medicine .
When the protective protein stops working
Two forms of the enzyme GRK2 occur in cells: a normal, functional form and a form that has been inactivated by the cellular metabolism. Quitterer and her team discovered that the inactivated form occurs in large quantities in the brain tissue of dementia patients. They were able to demonstrate the same thing in mice – specifically in a mouse model for Alzheimer's disease.
The researchers also showed that the inactive form of this enzyme forms aggregates in brain cells in the event of dementia. These aggregates deposit on – and damage – the mitochondria (the "powerhouses" of the cells). "The GRK2 aggregates block the pores of the mitochondria, reducing the amount of energy they can supply and leading to a situation of stress inside the cells," Quitterer explains.
In experiments on mice, the researchers also observed that the inactive GRK2 promotes the production of amyloid beta, a protein fragment that is considered a main cause of Alzheimer's.
What's more, this leads to a self-perpetuating process: amyloid beta puts stress on the nerve cells and, in turn, this stress leads to the formation of more inactive and aggregated GRK2 – creating a vicious circle that contributes to the progression of dementia.
Anti-ageing effect
With a view to breaking this vicious circle, Quitterer and her colleagues developed several chemical compounds, which they tested in cell culture experiments and on mice. Here, compound 10 proved to be particularly effective, preventing the GRK2 molecules from forming aggregates. As a result, the mitochondria work better, there is less deposition of amyloid beta in the cells, and the nerve cells maintain their function and do not die off.
In the mice, the team also observed effects outside the brain. Compound 10 had a positive influence on heart function and ageing processes. For example, the animals developed fewer grey hairs in old age.
Why the research took so long
The researchers have applied for a patent on compound 10, and the basic research is now complete. "It took so long simply because everything takes so long in Alzheimer's research," explains Quitterer. As the researchers were investigating an age-related disease, they worked with older animals. For mice, this means an age of one and a half to two years. And it takes about one and a half to two years to complete each experiment from which conclusions can be drawn that then lead to the planning of the next experiment. "It's all a great deal slower than in cancer research, for example."
Now, Quitterer and ETH Zurich are looking for a company that is interested in taking the next steps towards developing a drug.
"Alzheimer's is a very complex disease," says Quitterer. Current medications do not cure the disease, but rather – at most – delay its progression by several months. "That's why it's so important that we've now identified a new target protein in the form of GRK2, as well as an active ingredient that operates via GRK2 and therefore via a different mechanism than existing Alzheimer's drugs." Using compound 10 in combination with other medications, it may one day be possible to improve quality of life for patients.
