Skeptic Society Magazine

Researchers have identified a specific enzyme that clumps up and damages cellular powerhouses in the brains of mice with Alzheimer’s disease. Developing chemical compounds to prevent or eliminate these clumps slowed memory loss and brain cell death in the animals. The findings were published in Cell Reports Medicine.

Alzheimer’s disease involves the buildup of misfolded proteins in the brain, most notably beta-amyloid plaques and tau tangles. These proteins interfere with brain cell function and eventually lead to memory loss and cognitive decline.

A lesser-known player in cell survival is an enzyme called G-protein-coupled receptor kinase 2, or GRK2. In healthy cells, this enzyme usually operates in the main fluid of the cell, where it helps regulate cellular communication and stress responses.

When modified by a specific chemical tag in a process called phosphorylation, GRK2 changes its behavior. It can migrate to mitochondria, the microscopic structures that generate energy for cells.

A research team led by Joshua Abd Alla and Ursula Quitterer at ETH Zurich in Switzerland investigated whether abnormal regulation of this enzyme contributes to the brain damage seen in Alzheimer’s disease. Mitochondrial dysfunction is a major feature of the condition, and the researchers suspected that modified GRK2 might be interfering with these cellular powerhouses.

The team first examined the brain tissue of genetically modified mice that develop Alzheimer’s-like symptoms. They looked specifically at older mice that already exhibited heavy beta-amyloid buildup.

They found that a massive portion of the GRK2 in these mice had clumped together into large, dysfunctional aggregates. These clumps were highly concentrated on the mitochondria within the brain cells of the animals.

When the researchers looked at brain tissue samples from a small study of four human patients with dementia likely caused by Alzheimer’s, they observed the exact same pattern of clumped GRK2. In both the mice and the human samples, the accumulation of this enzyme was accompanied by mitochondrial dysfunction and elevated oxidative stress.

The researchers noted that the presence of beta-amyloid and toxic tau proteins actually triggered the initial phosphorylation and clumping of GRK2 in laboratory models. This suggests a destructive cycle where Alzheimer’s hallmark proteins damage mitochondria by causing GRK2 to clump, which in turn accelerates the buildup of more Alzheimer’s proteins.

To understand how the clumped enzyme causes damage, the researchers analyzed which other proteins it bound to in the mouse brains. They discovered that it attached to a protein called TOMM6, which normally helps transport materials across the outer membrane of mitochondria.

The researchers then tested the chemical interaction between GRK2 and TOMM6 in laboratory dishes. They observed that active, healthy GRK2 typically adds a chemical tag to TOMM6, keeping it stable and functional.

The clumped, modified version of GRK2 found in the diseased brains was inactive and failed to modify TOMM6. Without this chemical tag, TOMM6 also began to clump up and lose its ability to interact with the mitochondrial pores.

The scientists next bred new strains of mice to genetically force different versions of the GRK2 enzyme into their brains. When they introduced an inactive, clumping version of GRK2, the mice developed severe mitochondrial damage, rapid beta-amyloid accumulation, and died at an accelerated rate.

Conversely, breeding mice to produce extra active, healthy GRK2 protected the animals against these symptoms and improved their survival. In another genetic test, the researchers engineered mice to produce extra TOMM6 to compensate for the amount lost to clumping.

While extra TOMM6 reduced the large plaques of beta-amyloid, it unexpectedly caused a different, soluble form of beta-amyloid to build up. This soluble buildup was highly toxic to the brain cells, leading to an increased mortality rate in the animals.

Because simply adding TOMM6 was harmful, the team tried a pharmacological approach to fix the root of the problem. They developed a small chemical compound called CPD10, designed to stabilize GRK2 and prevent it from adopting the harmful, clumping shape.

Using computer modeling, the researchers found that CPD10 preferentially attaches to the healthy, unphosphorylated form of GRK2. By binding to this active form, the compound shifts the cellular balance, making it much harder for the enzyme to become phosphorylated and clump together.

They administered this compound to aging Alzheimer’s mice over a six-month period. The compound successfully penetrated the brain and prevented the enzyme from clumping on the mitochondria.

The mice treated with CPD10 had healthier mitochondria, fewer beta-amyloid plaques, less toxic tau protein, and experienced less brain cell loss than untreated mice. Behavioral tests in a water maze showed that the treated mice also retained better spatial memory.

The researchers explored a second chemical strategy aimed at removing the existing clumps rather than preventing new ones. They synthesized another molecule, CPD57, designed to boost the activity of the proteasome, which acts as the garbage disposal system of the cell.

Cells naturally use the proteasome to break down damaged or unnecessary proteins, preventing toxic buildups. The CPD57 compound physically binds to the opening of this disposal system, acting like a gate opener to let more waste inside.

They treated older Alzheimer’s mice with this compound for 14 days and evaluated their brain tissue. The compound increased the cellular garbage disposal activity and successfully degraded the clumped GRK2 and TOMM6 proteins.

When given over a six-month period, this molecule also slowed the accumulation of beta-amyloid plaques and reduced signs of cellular aging. The findings demonstrate that targeting these protein clumps from multiple pharmacological angles can offer neurological protection in animal models.

While these chemical compounds showed promising results in mice, animal models of Alzheimer’s disease do not perfectly replicate the human condition. The human tissue analysis in this study relied on a very limited number of brain samples obtained during surgery for brain tumors.

Because these samples were taken during active operations rather than after death, they provided a rare snapshot of the living brain’s chemistry, but the sample size was inherently small. Larger studies involving more human patients are necessary to confirm how widespread this specific enzyme clumping is in the general population.

It remains an open question whether the clumped enzyme on the mitochondria is the primary driver of the brain damage, or if the overall lack of healthy, active GRK2 floating elsewhere in the cell is the real culprit. Future research using organisms entirely deficient in GRK2 will help pinpoint the exact mechanism behind the cellular deterioration.

Extensive safety and efficacy testing will be required before either of the newly developed chemical compounds can be considered for human clinical trials. These findings provide 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.