Researchers are developing compound 10 to slow the progression of Alzheimer’s disease

Researchers from ETH Zurich have developed an active ingredient that slows the progression of typical Alzheimer’s symptoms in mice. This new substance protects nerve cells and could in the future ease the suffering of Alzheimer’s patients. The active ingredient also has anti-aging effects.

“Compound 10” is how Ursula Quitterer refers to the chemical compound her team has developed that could slow the progression of Alzheimer’s disease. Quitterer is Professor of Molecular Pharmacology at ETH Zurich and has so far tested the active ingredient first in mice, revealing promising results: the typical death of nerve cells seen in dementia is significantly slower and the animals survive longer.

The new substance is the result of research that began nearly 20 years ago, when Quitterer obtained tissue samples from patients of a doctor and colleague at Ain Shams University Hospital in Cairo. These were samples of brain tissue that the doctor had removed during tumor surgery – both from people diagnosed with dementia and from patients without dementia.

New point of attack for drugs

Quitterer started working on these samples – but to understand exactly what she did with them, we first need a little background. Then, as now, the main focus of her research was a somatic enzyme that plays a vital role in many human cells: GRK2. As a regulatory protein, this enzyme helps cells respond properly to signals, stress and strain. As in the heart, for example, it is also active in the brain – where it supports the function of nerve cells.

Through molecular analyzes of tissue samples from Cairo and research in mice, Quitterer’s team showed how important 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 GRK2 enzyme occur in cells: a normal, functional form and a form that has been inactivated by cellular metabolism. Quitterer and her team discovered that the inactivated form appears in large amounts in the brain tissue of dementia patients. They were able to demonstrate the same thing in mice – specifically in a mouse model of Alzheimer’s disease.

The researchers also showed that the inactive form of this enzyme forms aggregates in brain cells in dementia. These aggregates deposit in – and destroy – mitochondria (the ‘powerhouses’ of cells).

GRK2 aggregates block mitochondrial pores, reducing the amount of energy they can provide and leading to a state of stress within the cells.”

Ursula Quitterer, ETH Zurich

In experiments on mice, the researchers also observed that inactive GRK2 promoted the production of amyloid beta, a protein fragment thought to be the main cause of Alzheimer’s disease.

Furthermore, this leads to a self-perpetuating process: beta amyloid puts stress on nerve cells and, in turn, this stress leads to the formation of more inactive and concentrated GRK2 – creating a vicious cycle that contributes to the progression of dementia.

Anti-aging action

In order to break this vicious cycle, Quitterer and her colleagues developed several chemical compounds, which they tested in cell culture experiments and in mice. Here, compound 10 proved particularly effective, preventing GRK2 molecules from forming aggregates. As a result, mitochondria work better, there is less beta amyloid deposition in cells, and nerve cells maintain their function and do not die.

In mice, the team also observed effects outside the brain. Compound 10 had a positive effect on heart function and aging processes. For example, animals developed fewer gray hairs in old age.

Why did the investigation take so long?

The researchers have applied for a patent for compound 10 and basic research is now complete. “It took so long simply because everything takes so long in Alzheimer’s research,” explains Quitterer. As the researchers investigated an age-related disease, they worked with older animals. For mice, this means one and a half to two years of age. 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 much slower than in cancer research, for example.”

Now, Quitterer and ETH Zurich are looking for a company interested in taking the next steps towards developing a drug.

“Alzheimer’s is a very complex disease,” says Quitterer. Current drugs do not cure the disease, but – at most – delay its progression by several months. “This is why it is so important that we have now identified a new target protein in the form of GRK2, as well as an active ingredient that works through GRK2 and therefore through a different mechanism than existing Alzheimer’s drugs.” By using compound 10 in combination with other drugs, it may one day be possible to improve patients’ quality of life.