In a study published in Cell Reports Medicinethe team of Professor Ursula Quitterer, from ETH Zurich, shows that an enzyme called GRK2 plays a central role in a vicious circle that accelerates brain degeneration. By blocking this process using a molecule called “Compound 10”, researchers managed to slow the progression of Alzheimer-type symptoms in mice. A discovery that opens a completely different path from that of currently available treatments.
A little-known enzyme at the heart of a destructive cycle
For decades, Alzheimer’s research has focused primarily on the famous amyloid beta plaques that accumulate in patients’ brains. However, despite recent advances, treatments targeting this protein only offer limited benefits and do not stop the disease.
At ETH Zurich, researchers chose to explore another avenue. Their attention focused on an enzyme called GRK2, present in particular in the brain and the heart. Normally, this protein plays an essential role: it helps cells respond to biological signals and cope with stress.
But the Swiss team discovered that an inactive version of this enzyme accumulates in large quantities in brains with dementia. This altered form ends up clumping together and clinging to mitochondria, the structures that produce the energy essential for neurons to function.
“GRK2 aggregates block the pores of mitochondria, reducing the amount of energy they can provide and creating a stressful situation inside the cells.explains Ursula Quitterer, professor of molecular pharmacology at ETH Zurich.
The consequences are considerable. Deprived of energy, neurons become more vulnerable and their functioning gradually deteriorates.
Researchers also observed that this inactive form of GRK2 promotes the production of amyloid beta, one of the proteins most involved in Alzheimer’s disease. This accumulation of amyloid in turn increases cellular stress, leading to the formation of new GRK2 aggregates. A real vicious circle then sets in, accelerating the progression of the disease.
“Compound 10”: a molecule that breaks the vicious circle in mice
Faced with this mechanism, scientists looked for a way to interrupt this harmful cascade. After developing several chemical compounds and testing them on cell cultures and then on animal models, one candidate clearly stood out: “Compound 10”.
Administered for several months to mice genetically modified to develop characteristics similar to Alzheimer’s disease, the molecule produced particularly encouraging results.
By preventing GRK2 molecules from aggregating, Compound 10 allowed mitochondria to return to more normal functioning. Amyloid beta deposits decreased, neurons retained their function longer and their death was significantly slowed. The treated animals also lived longer than the untreated mice.
Even more surprising, the observed benefits were not limited to the brain. Researchers have found improved heart function as well as some effects associated with healthier aging. Among the observations reported: treated mice developed less gray hair during aging.
However, these results remain confined to the laboratory. No human trials have yet been carried out, and it is impossible to know at this stage whether the effects observed in mice will be reproduced in patients.
A hopeful discovery, but a long journey before treatment
For Ursula Quitterer, the major interest of this discovery lies in its originality. Unlike current drugs, which mainly target amyloid beta, Compound 10 acts on a different mechanism: the protection of the energetic functioning of neurons via the GRK2 enzyme.
“Alzheimer’s disease is very complex”recalls the researcher. “Current medications do not cure the disease, but at best delay its progression for a few months..
She adds: “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 acts via GRK2 and therefore by a different mechanism than existing Alzheimer’s drugs.“.
Today, the team has filed a patent and is looking for an industrial partner who can continue the development of the drug. The next steps will be long: safety studies, additional preclinical trials then, possibly, clinical trials in humans.
For the millions of families facing Alzheimer’s, this discovery does not yet represent a treatment. It nevertheless provides something valuable: a new understanding of the mechanisms of the disease and proof that beyond amyloid, other therapeutic targets remain to be explored. In a field where progress is often measured in years, the identification of this new path could help design the combined treatments of tomorrow and, perhaps, one day offer more time and quality of life to patients.