Scientists from the Swiss Federal Institute of Technology Zurich (ETH Zurich) have discovered that in Alzheimer's disease a clumped enzyme, GRK2 (short for G protein-coupled receptor kinase 2), accumulates in the brain. Enzymes are proteins that speed up chemical reactions in the cell. GRK2 clumps settle on mitochondria, the microscopic "power plants" of the cell, and disrupt their function. The results of the study were published in the journal Cell Reports Medicine.
Normally GRK2 is located in the cell's main fluid and helps regulate its communication and response to stress. However, with a certain chemical change - phosphorylation (the attachment of a phosphate group) - the enzyme changes behavior and can move to the mitochondria.
A team led by Joshua Abd Alla and Ursula Quitterer studied genetically modified mice with symptoms resembling Alzheimer's disease. In older animals with abundant deposits of beta-amyloid (a protein that forms plaques in the brain), a significant portion of GRK2 was clumped into large nonfunctional aggregates concentrated on mitochondria. The scientists saw the same pattern in brain tissue samples from four patients with dementia probably caused by Alzheimer's disease. In both cases the clumps were accompanied by mitochondrial dysfunction and increased oxidative stress - damage to cells by aggressive forms of oxygen.
Experiments showed that beta-amyloid and the toxic protein tau trigger the phosphorylation and clumping of GRK2. This creates a vicious circle: the disease's "calling card" proteins damage mitochondria through GRK2 clumps, and these accelerate the accumulation of new amyloid and tau.
Clumped GRK2 loses the ability to attach a chemical tag to the protein TOMM6, which usually helps transport substances across the outer membrane of mitochondria. Without this tag, TOMM6 also clumps and stops working.
When the researchers genetically forced the brains of mice to produce an inactive, clump-prone GRK2, the animals suffered severe mitochondrial damage, rapid accumulation of beta-amyloid and died earlier. By contrast, additional active GRK2 protected the mice and improved survival. Adding extra TOMM6 reduced large plaques but unexpectedly led to the accumulation of soluble beta-amyloid, which is toxic to cells, and increased mortality.
The scientists then developed the compound CPD10, which stabilizes the healthy form of GRK2 and prevents it from clumping. Six months of treatment in old mice with an Alzheimer's model led to healthier mitochondria, fewer amyloid plaques and tau clumps, and less death of brain cells. In a water maze, such mice retained spatial memory better.
A second approach is the compound CPD57, which enhances the work of the proteasome, the cell's "garbage incinerator". It helps destroy already existing clumps of GRK2 and TOMM6. After 14 days of treatment, the mice's clearance activity increased, and with a six-month course the accumulation of plaques and signs of cellular aging slowed.
The authors emphasize limitations: the mouse model does not fully replicate the human disease, and the analysis of human tissue relied on only four samples obtained during surgery to remove brain tumors. In addition, it remains unclear what exactly is the main culprit of the damage - clumped GRK2 on mitochondria or a general shortage of the healthy enzyme in the cell. Before clinical trials in humans, the new compounds must undergo large-scale safety and efficacy checks.