A protein that normally helps cells handle everyday signals may become harmful in dementia, according to new research from ETH Zurich.
Scientists have also created an experimental chemical that blocks this harmful change and protected brain cells in mice.
The chemical is called Compound 10. Research led by ETH Zurich molecular pharmacologist Ursula Quitterer was published in Cell Reports Medicine.
Alzheimer’s disease develops slowly, often over many years before severe memory problems become obvious. During that time, nerve cells face several forms of stress and gradually lose their ability to communicate and survive.
Researchers have spent decades studying amyloid beta, a protein that can form deposits in the Alzheimer’s brain. Yet Alzheimer’s involves much more than one protein, which is why scientists continue searching for other processes that could be targeted with medicines.
Quitterer’s team turned its attention to GRK2. This enzyme works in many cells throughout the body and helps control how cells react to chemical messages and stressful conditions.
The investigation has unusually long roots. Nearly two decades ago, Quitterer obtained brain samples from patients at Ain Shams University Hospital in Cairo after tissue had been removed during surgery for brain tumors.
Some of the patients had dementia and others did not. Comparing their tissue gave the researchers an opportunity to look for biological differences that might help explain what happens inside the brain during dementia.
They discovered that GRK2 could exist in a normal working state or in an inactive state created through processes inside cells. Brain tissue from people with dementia contained particularly large amounts of the inactive version.
The same pattern appeared when the researchers studied mice designed to develop Alzheimer’s-like disease. More importantly, the inactive GRK2 did not simply stop doing its normal job.
It began gathering into clusters. The researchers found these GRK2 clusters around mitochondria, the small structures that act as energy-producing centers inside cells.
The brain consumes enormous amounts of energy, and nerve cells depend heavily on healthy mitochondria. When these energy systems fail, neurons can become stressed and may eventually die.
According to the study, GRK2 clusters interfered with openings in mitochondria and reduced their ability to work normally. That left the cells under greater stress and created an environment in which further damage could develop.
The researchers then found another troubling effect. Inactive GRK2 was linked to increased production of amyloid beta, adding a second source of stress for vulnerable nerve cells.
This could create a self-reinforcing loop. More inactive GRK2 could lead to more amyloid beta and cellular stress, while that additional stress could encourage even more GRK2 to become inactive and form clusters.
To find a way out of this loop, the scientists developed and tested a series of experimental chemicals. One candidate, Compound 10, was particularly good at stopping GRK2 molecules from sticking together.
In treated mice, mitochondria functioned better and amyloid beta buildup was reduced. The researchers also reported slower nerve-cell death and longer survival in animals receiving the compound.
The results went beyond dementia-related changes. The treatment appeared to have beneficial effects on the animals’ hearts and on some visible features of aging, with older treated mice developing less grey hair.
That does not mean Compound 10 is an anti-aging drug. Instead, the observation suggests that GRK2 and mitochondrial stress may be involved in biological processes that affect several organs as animals grow older.
Developing Alzheimer’s medicines is particularly slow because age itself is a central part of the disease. Researchers often need to wait until experimental animals are old before they can study the changes they are interested in, meaning a single round of experiments can take years.
Quitterer’s group says the basic research stage for Compound 10 has been completed, and patent protection has been sought. ETH Zurich and the researchers are now looking for an industry partner that could help take the experimental drug through the next stages of development.
Those next steps are crucial. Before a drug can become available to patients, scientists must investigate how it moves through the body, whether enough of it reaches the brain, what dose is safe, and whether it causes harmful effects.
Human trials would then need to determine whether the compound actually slows memory loss or other symptoms. Many treatments that look impressive in mouse studies do not ultimately work in people, so the current findings should not be interpreted as evidence of a cure.
Even with that caution, the research has an important strength. It identifies a biological target that is different from the targets of many existing Alzheimer’s drugs and connects that target with energy failure, amyloid production, and nerve-cell survival.
This matters because Alzheimer’s probably will not be solved by a single strategy. Future care may require combinations of medicines that attack different parts of the disease, much as doctors use several approaches to manage other complex illnesses.
Compound 10 could eventually become one part of such a strategy if later studies are successful. Its value may lie in protecting mitochondria and preventing harmful GRK2 clusters while other treatments address amyloid or different disease processes.
For now, the study should be viewed as promising early-stage research rather than an imminent treatment. It gives scientists a fresh target to investigate, but only careful safety studies and clinical trials can show whether the encouraging results in mice translate into real benefits for people with Alzheimer’s disease.
Source: ETH Zurich.
