A mutation causes cognitive decline: a potential new target for Alzheimer's disease

In 2016, a genome-wide sequencing of genetic factors for Alzheimer's disease identified mutations in protein kinase C (PKCα) that were associated with the disease. Among these, the M489V mutation was only found in family members affected by Alzheimer's disease. Therefore, the effect of M489V mutation, protein kinase C, on Alzheimer's disease began to receive attention.

Previous studies have noted that the M489V mutation can boost protein kinase C activity by about 30%, but what is not clear to the scientific community is how such a change would affect the pathology of Alzheimer's disease.

In a study published in Nature Communications, a team led by Professor Alexandra Newton at the University of California, San Diego, found that just a slight boost in protein kinase C activity was enough to cause biochemical, cellular-level changes, as well as cognitive impairment, in the brains of mice—changes that are similar to those seen in human patients with Alzheimer's disease. Thus, protein kinase C is expected to be a novel therapeutic target for Alzheimer's disease.

Protein kinase C regulates the function of a variety of proteins, especially in the brain. This enzyme allows the phosphorylation of substrate protein molecules, enhancing the activity of the protein and its ability to bind to other molecules. In the brain, by regulating the phosphorylation state of proteins in the synapse, protein kinase C is likely to play an important role in the transmission of neural signals.

To analyze the role of protein kinase C in Alzheimer's disease, the team constructed mouse models of the M489V mutation in protein kinase C and monitored their biochemical indicators and behavioral changes for more than a year thereafter.

These mice demonstrated significant alterations in protein phosphorylation levels in the brain at 3 months, indicating aberrant neuronal protein regulation. At 4.5 months, neurons in the mice's hippocampus had cellular-level alterations such as decreased synaptic inhibition and dendritic spine density. The mice had lower performance on spatial learning and memory tests after 12 months, indicating unequivocal evidence of cognitive loss in the mice.

"We were surprised to see that a slight increase in protein kinase C activity was enough to reproduce the symptoms of Alzheimer's disease in a mouse model," Professor Newton said. "This finding makes a case for the importance of endostasis, where even fine-tuning enzyme activity can accumulate over time to induce pathological symptoms."

Following the completion of the mouse trial, the team wanted to know if similar changes were observed in human patients. They did this by examining the frontal cortex of the brains of deceased Alzheimer's patients. These brains had an average of 20% greater protein kinase C levels than subjects without the disease. Furthermore, the phosphorylation levels of recognized substrate proteins were increased by around threefold, indicating the enhanced protein kinase C activity in Alzheimer's disease patients.

The researchers noted that there are many mutations besides the M489V mutation that can cause abnormalities in protein kinase C. These mutations may be able to regulate protein kinase C in a similar pathway and induce Alzheimer's disease.

A variety of protein kinase C inhibitors are currently used for cancer treatment, which may be able to be repurposed for Alzheimer's disease treatment.