Experimental Alzheimer’s Drug Candidate Slowed Disease Progression In Mice And Appeared To Slow Aging

New Alzheimer’s Drug Candidate Targets a Different Mechanism Than Existing Treatments

Most Alzheimer’s drug development has focused on the same target: the sticky plaques that accumulate in the brain. A new study from ETH Zurich, the product of nearly 20 years of work, points to a different culprit operating deeper inside brain cells, and the experimental compound developed to address it did something researchers had not anticipated. Besides slowing disease progression in mice, it appeared to slow aging.

Scientists at ETH Zurich and partner institutions found that GRK2, a protein that normally helps brain cells survive and respond to stress, misfires badly in the Alzheimer’s brain. When it malfunctions, it clumps into dysfunctional masses on the mitochondria, the tiny power-generating structures inside cells. Published in Cell Reports Medicine, the study shows that clumping sets off a chain reaction draining cellular energy, worsening the plaques that define Alzheimer’s, and killing neurons.

In the brains of aged Alzheimer’s mice, more than 63% of GRK2 in the hippocampus, the brain region essential for memory, had clumped into dysfunctional masses, compared to less than 9% in healthy mice. Similar clumping also appeared in brain tissue from a small number of patients with dementia likely due to Alzheimer’s, suggesting, but not proving, the process may occur in people.

Defective GRK2 Clogs Brain Cell Power Plants and Accelerates Plaque Formation

GRK2 exists in two forms: a normal, functioning version and a chemically altered, inactive form. In Alzheimer’s, the disease’s hallmark proteins, amyloid-beta and tau, trigger a chemical change that inactivates GRK2 and causes it to clump. Those clumps migrate to the mitochondria, where they trap a second protein called TOMM6 and render it useless. “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.

That stress creates more amyloid-beta. More amyloid-beta triggers more inactive, clumped GRK2, which clamps down harder on the mitochondria. A feedback loop quietly accelerates the disease.

CPD10 Reduced Alzheimer’s Damage in Mice and Slowed Cellular Aging

To break that loop, Quitterer’s team developed a compound they call Compound 10, or CPD10, engineered to stabilize the healthy form of GRK2 and clear out the dysfunctional clumps. It crossed into the brain effectively, reaching roughly the same concentration there as in the blood. After six months of treatment in Alzheimer’s mice, CPD10 dramatically reduced GRK2 clumping on mitochondria, restored energy production, cut amyloid-beta plaques, and lowered markers of brain inflammation. Treated mice showed less nerve cell loss, better spatial memory, and longer survival than untreated Alzheimer’s mice.

More surprisingly, CPD10 appeared to slow aging beyond the brain. Treated mice showed improved heart function, and in a striking detail, developed fewer gray hairs in old age than untreated animals. Consistent with that, the compound significantly reduced UPAR, a biological marker of cellular aging, in treated mice.

A second compound, CPD57, targeted the cell’s protein cleanup system, which malfunctions in Alzheimer’s and lets damaged proteins pile up. Short-term treatment accelerated the breakdown of defective GRK2 clumps; six months of treatment reduced amyloid-beta plaques, and CPD57-treated mice also survived longer than untreated animals.

ETH Zurich Is Seeking a Partner to Advance CPD10 Toward Human Development

With the basic research now complete and a patent application filed, Quitterer and ETH Zurich are actively looking for a pharmaceutical company to take the next steps. The motivation, she says, is clear. “Current medications do not cure the disease, but rather, at most, delay its progression by several months,” Quitterer says. “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.”

All animal experiments were conducted in genetically engineered mice, and results in mouse models frequently fail to translate to people. Human tissue data from a small number of patients serve as supporting observations, not clinical proof.

Still, a compound that targets a new mechanism, crosses into the brain, slows neurodegeneration, extends survival, and appears to slow aging in mice gives researchers an unusually specific thread to pull in a disease that has no cure.

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Disclaimer: This article is based on peer-reviewed animal research and information from an institutional press release. Findings from mouse studies do not always translate to humans, and neither CPD10 nor CPD57 has been tested in human clinical trials. This content is for informational purposes only and is not intended as medical advice.

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