Researchers at ETH Zurich, led by Joshua Abd Alla and Ursula Quitterer, have identified a misbehaving enzyme—GRK2—that forms large clumps on mitochondria in the brains of mice engineered to model Alzheimer’s disease. The clumps align with mitochondrial dysfunction and oxidative stress, and the team reports that chemical compounds designed to prevent or dissolve them slowed brain cell death and memory decline in the animals. The findings appear in Cell Reports Medicine.
In healthy cells, GRK2 normally operates in the cytosol, where it helps regulate cellular communication and stress responses. When a specific phosphate tag is added, GRK2 can migrate to the mitochondria, the tiny powerhouses that generate energy for the cell.
The ETH Zurich team studied brain tissue from older genetically modified mice that develop Alzheimer’s-like pathology and heavy beta-amyloid buildup. They found that a substantial portion of GRK2 had clumped into large aggregates and was highly concentrated on the mitochondria within brain cells.
They also examined brain tissue from a small study of four human patients with dementia likely caused by Alzheimer’s disease and observed the same pattern of GRK2 clumping, accompanied by mitochondrial dysfunction and elevated oxidative stress. The researchers noted that beta-amyloid and toxic tau proteins appeared to trigger the initial phosphorylation and clumping of GRK2 in laboratory models, suggesting a destructive cycle that worsens mitochondrial damage and accelerates Alzheimer’s pathology.
To understand how the clumped enzyme causes harm, the researchers assessed which other proteins GRK2 binds to in mouse brains and found an interaction with TOMM6, a protein that normally assists transport across the outer mitochondrial membrane. In laboratory tests, active, healthy GRK2 typically adds a chemical tag to TOMM6, keeping it stable and functional.
In contrast, the clumped, altered form of GRK2 found in diseased brains was inactive and failed to modify TOMM6. Without this regulatory tag, TOMM6 began to clump and lost its ability to interact with the mitochondrial pores, potentially disrupting energy production and cellular health.
The team then bred new mouse strains to express different versions of GRK2 in the brain. When they forced an inactive, clumping GRK2 into the brain, the mice developed severe mitochondrial damage, rapid beta-amyloid accumulation, and died earlier. Conversely, mice engineered to produce extra active GRK2 showed protection against these symptoms and improved survival.
In an additional genetic test, researchers engineered mice to produce more TOMM6 to compensate for the loss caused by GRK2 clumping. While extra TOMM6 reduced large beta-amyloid plaques, it unexpectedly allowed a soluble form of beta-amyloid to accumulate, which proved highly toxic to brain cells and increased mortality.
To address the root cause pharmacologically, the team developed a small molecule named CPD10, designed to stabilise GRK2 and prevent its harmful clumping. Computer modelling suggested CPD10 preferentially binds the healthy, unphosphorylated form of GRK2, biasing the balance away from clumping.
When aged Alzheimer’s-model mice were treated with CPD10 for six months, the compound crossed into the brain and prevented GRK2 from aggregating on mitochondria. Treated mice displayed healthier mitochondria, fewer beta-amyloid plaques, reduced toxic tau, less brain cell loss, and better performance in a water maze assessing spatial memory.
As a second approach, the researchers created CPD57 to boost the proteasome, the cell’s waste disposal system, with the aim of removing existing clumps. In older mice treated for 14 days, CPD57 increased proteasome activity and degraded the clumped GRK2 and TOMM6. Over six months, the compound slowed beta-amyloid plaque accumulation and reduced signs of cellular aging, indicating multiple avenues to target these protein clumps.
However, the researchers caution that animal models do not perfectly mirror the human condition. The human tissue analysis relied on a very small sample gathered during brain tumour operations, offering a rare living-brain snapshot but limiting broad conclusions. Larger studies are needed to determine how widespread GRK2 clumping is in people with Alzheimer’s disease.
It remains unclear whether the mitochondrial clumps are the primary driver of brain damage or whether a broader deficiency of healthy GRK2 elsewhere in the cell is the real culprit. Future work may involve examining organisms completely deficient in GRK2 to resolve the mechanism at play.
Extensive safety and efficacy testing will be required before either CPD10 or CPD57 can advance to human clinical trials. Nevertheless, the researchers say the work provides a new pharmacological avenue to protect the aging brain.
The study, “Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models,” was authored by Joshua Abd Alla, Alexander Perhal, Xuebin Fu, Andreas Langer, Yasser el Faramawy, and Ursula Quitterer.
