Ursula Quitterer calls it “Compound 10,” a chemical substance developed by her research team that could potentially slow the progression of Alzheimer’s disease.
Quitterer, Professor of Molecular Pharmacology at ETH Zurich, has so far tested the experimental treatment in mice. The results were encouraging. The nerve cell death typically associated with dementia slowed significantly, and the treated animals lived longer.
The work behind the compound began nearly 20 years ago, when Quitterer received brain tissue samples from patients treated by a doctor and colleague at Ain Shams University Hospital in Cairo. The tissue had been removed during tumor surgery from people with dementia as well as non-dementia patients.
A New Drug Target in Alzheimer’s Disease
Quitterer used those samples to investigate an enzyme called GRK2, which has long been a major focus of her research.
GRK2 plays an important regulatory role in many human cells. It helps cells respond appropriately to signals, stress, and strain. The enzyme is active in organs including the heart and the brain, where it helps support normal nerve cell function.
By analyzing the Cairo tissue samples at the molecular level and conducting experiments in mice, Quitterer and her colleagues uncovered evidence that GRK2 plays an important role in dementia. Their findings were recently published in the journal Cell Reports Medicine.
What Happens When GRK2 Stops Working
GRK2 exists in cells in two forms. One is normal and functional, while the other has been inactivated by cellular metabolism.
Quitterer’s team found unusually large amounts of the inactive form in brain tissue from people with dementia. The researchers observed the same pattern in mice, specifically in a mouse model for Alzheimer’s disease.
They also discovered that inactive GRK2 can clump together inside brain cells during dementia. These aggregates collect on mitochondria (the “powerhouses” of the cells), where they can interfere with normal function and cause damage.
“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.
The mouse experiments revealed another important effect. Inactive GRK2 appeared to increase production of amyloid beta, a protein fragment that is considered a main cause of Alzheimer’s.
That process can then feed back on itself. Amyloid beta places additional stress on nerve cells, and that stress encourages the formation of more inactive GRK2 and more GRK2 aggregates. The result is a vicious circle that can contribute to the progression of dementia.
Compound 10 Breaks the Harmful Cycle
To interrupt this process, Quitterer and her colleagues created several chemical compounds and tested them in cell cultures and mice.
Compound 10 stood out as particularly effective. It prevented GRK2 molecules from forming aggregates, which allowed mitochondria to function better. The researchers also saw less amyloid beta accumulating in cells, while nerve cells were better able to maintain their function and avoid dying.
The effects were not limited to the brain.
In mice, compound 10 also had a positive effect on heart function and aging processes. One visible example was that older animals developed fewer grey hairs.
An Unexpected Effect on Aging
The broader effects of compound 10 suggest that interfering with GRK2 aggregation may influence more than Alzheimer’s related processes.
In addition to protecting nerve cells and supporting mitochondrial function, the compound appeared to benefit the heart and affect some signs of aging in the mice.
These findings remain preclinical, however. Compound 10 has not yet been developed into a treatment for people.
Why Alzheimer’s Research Takes Years
The researchers have applied for a patent covering compound 10, and the basic research phase has now been completed.
“It took so long simply because everything takes so long in Alzheimer’s research,” explains Quitterer.
Because Alzheimer’s is an age-related disease, the team needed to conduct experiments using older animals. In mice, that means working with animals that are about one and a half to two years old.
Each experiment can also require roughly one and a half to two years before researchers have enough information to draw conclusions and design the next study.
“It’s all a great deal slower than in cancer research, for example.”
Quitterer and ETH Zurich are now searching for a company interested in helping move the compound toward the next stages of drug development.
A Different Approach to Treating Alzheimer’s
“Alzheimer’s is a very complex disease,” says Quitterer.
Existing medications do not cure Alzheimer’s. At best, they can 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.”
Because compound 10 acts through a different biological pathway, the researchers believe it could potentially complement existing treatments rather than replace them.
Using compound 10 alongside other medications may one day help improve quality of life for people with Alzheimer’s disease.
