A Swiss study has discovered a previously underestimated mechanism in Alzheimer's disease and developed a compound that can interrupt it. The study was published in the journal Cell Reporting Medicine.
According to the science website "SciTechDaily", for decades, research on Alzheimer's disease has mainly focused on amyloid plaques and tau proteins, which are abnormal proteins that accumulate in the brain as the disease progresses. Now a team of researchers at ETH Zurich, Switzerland, has discovered that a little-known cellular protein, GRK2, may be a driver of neurodegeneration and could become a new therapeutic target.
The search for GRK2 began nearly 20 years ago. Ursula Quitterer, a professor of molecular pharmacology at ETH Zurich at the time, obtained a brain tissue sample from a colleague at Ain Shams University Hospital in Cairo. The samples were obtained during oncology surgeries and included tissue from individuals with and without dementia. By comparing these tissues, Quittler and colleagues began looking for molecular differences that might reveal previously overlooked drivers of the disease.
Quettler and colleagues ultimately focused on GRK2, a protein that plays a key role in regulating cells' responses to signals and stress. Although GRK2 is found throughout the body, including in the heart and brain, it has received relatively little attention in Alzheimer's research.
Now the research team has discovered that GRK2 exists in two forms. One is the normal functional type, which helps cells maintain healthy messaging and respond to environmental changes; the other is the inactive type produced through normal cellular processes. Researchers noticed abnormally high amounts of inactive GRK2 in the brain tissue of dementia patients and in mouse models of Alzheimer's disease. What's more important is that the inactive eggs clump together and attach to mitochondria.
Mitochondria generate the energy needed for nearly all cellular processes, and neurons are particularly dependent on them because brain cells require large amounts of energy to maintain communication networks across vast brain regions. GRK2 aggregates block mitochondrial pores, reducing the energy they can provide and causing increased intracellular pressure. A growing number of researchers believe that mitochondrial dysfunction is one of the earliest events in neurodegenerative diseases.
The research team also found a link between inactive GRK2 and beta-amyloid, a protein highly associated with Alzheimer's disease. Experiments show that inactive GRK2 promotes the production of beta-amyloid. Beta-amyloid also puts additional stress on neurons, promoting the formation of more inactive GRK2 aggregates. This accelerated cycle may further promote brain damage and cognitive decline.
To stop this cycle, the team developed and tested a series of experimental compounds in cell cultures and mice, with Compound 10 showing the most promising results. This molecule prevents the aggregation of inactive GRK2 and helps maintain mitochondrial function. As mitochondrial health improves, beta-amyloid levels also decrease.
It is not yet certain whether GRK2 will have similar effects in humans, but research suggests that therapies targeting GRK2 may affect multiple age-related physiological processes. The research team has filed a patent application for compound 10 and completed the basic research needed to establish its potential.
