A promising experimental compound developed by researchers at ETH Zurich could offer a new way to slow the progression of Alzheimer’s disease. In studies on mice, the treatment reduced nerve cell loss, extended the animals’ lifespans, and targeted biological processes that cannot be addressed by existing Alzheimer’s disease drugs.
The compound, known to researchers as Compound 10, is the result of nearly 20 years of research led by Ursula Quitterer, a professor of molecular pharmacology at the Swiss Federal Institute of Technology Zurich.
Long study seeking new Alzheimer’s clues
The research began about 20 years ago when Quitterer received a brain tissue sample from a colleague at Cairo’s Ain Shams University Hospital. Samples were collected during tumor surgery and were taken from both patients with dementia and those without dementia.
These samples helped Quitterer begin studying a protein called GRK2, a longtime focus of his research.
GRK2 plays important roles throughout the body. As regulatory proteins, they help cells respond to signals and adapt to stress. It is active in several organs, including the heart and brain, and supports healthy nerve cell function.
Using both human brain tissue and a mouse model of Alzheimer’s disease, a team from ETH Zurich found evidence that GRK2 may be a major cause of dementia. Their findings were recently published in the journal cell report medicine.
When protective proteins turn harmful
GRK2 exists in two forms within cells. One form functions normally, while the other is rendered inactive by cellular processes.
Researchers found that the inactive version accumulates in large amounts in the brains of people with dementia. A similar pattern was observed in mice that developed Alzheimer’s disease-like symptoms.
Further experiments revealed that inactive GRK2 molecules aggregated within nerve cells. These clusters attach to mitochondria, structures often referred to as the cell’s “powerhouses”, and interfere with their function.
“GRK2 aggregates block the mitochondrial pores, reducing the amount of energy they can provide and creating a stress situation within the cell,” Quitterer explains.
The research team also found that inactive GRK2 appears to increase production of amyloid beta, a protein fragment widely associated with Alzheimer’s disease.
This creates a harmful cycle. Amyloid beta puts additional stress on nerve cells, leading to the formation of even more inactive GRK2. As more GRK2 accumulates and forms aggregates, the disease process continues to accelerate.
Compound 10 breaks the cycle
To interrupt this cycle, researchers designed several experimental compounds and tested them in cultured cells and mice.
Among them, compound 10 gave the most potent results. This compound prevented GRK2 molecules from forming harmful aggregates, allowing mitochondria to function more effectively. As a result, amyloid beta deposits were reduced, nerve cells remained healthier, and cell death slowed.
The benefits extended beyond the brain.
In mice, compound 10 appears to improve cardiac function and influence changes associated with aging. The researchers observed that treated animals had fewer gray hairs as they grew older.
Why the research took nearly 20 years
The research team has completed the basic research phase and filed a patent application for compound 10.
Quitterer said one reason the study took so long is the nature of Alzheimer’s disease research itself.
“The reason it took so long is because everything in Alzheimer’s disease research is so time-consuming,” Quitterer explains.
Because Alzheimer’s disease is an age-related disease, the researchers conducted their study in older mice. These animals were typically between 18 months and 2 years old. Each experiment took a similar amount of time to draw meaningful conclusions and begin the next phase of the study.
“It takes much longer than, say, cancer research.”
New targets for future Alzheimer’s disease treatment
ETH Zurich and the researchers are currently looking for companies interested in advancing compound 10 toward drug development.
“Alzheimer’s disease is a very complex disease,” Quitterer said. Current drugs do not cure the disease, but only slow its progression by a few months at most.
“That is why it is so important that we have identified a new target protein in the form of GRK2 and an active ingredient that acts through GRK2 and therefore by a different mechanism than existing Alzheimer’s drugs.”
Although more research is needed to test this compound in humans, this discovery opens the door to new therapeutic strategies. Researchers believe that combining Compound 10 with existing Alzheimer’s disease drugs could ultimately provide greater benefits and improve patients’ quality of life.
