Increased activity of mutant forms of a specific enzyme, protein kinase Cα (PKCα), correlates with damage to neurons caused by the amyloid-beta protein in late-onset Alzheimer’s disease, researchers from the University of California, San Diego, School of Medicine and Harvard Medical School reported. The findings also suggest that drugs inhibiting the enzyme, unsuccessful in cancer clinical trials, might have therapeutic value in AD.
The study, “Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease”, was published in Science Signalling.
Plaque deposits of insoluble, aggregated amyloid β (Aβ) peptide is one of the most important neuropathological hallmarks of Alzheimer’s disease, and its neurotoxicity has been correlated with neuronal and synaptic loss, which leads to the decline in cognitive function observed in Alzheimer’s patients. The PKC enzyme was, until recently, thought to help cells survive and, as a consequence, too much enzyme activity would promote cancer growth. Several PKC inhibitors tested as cancer treatments, however, did not work.
“Until recently, it was thought that PKC helped cells survive, and that too much PKC activity led to cancer. … Instead, we recently found that the opposite is true. PKC serves as the brakes to cell growth and survival, so cancer cells benefit when PKC is inactivated,” Dr. Alexandra Newton, the study’s lead author, said in a news release. “Now, our latest study reveals that too much PKC activity is also bad, driving neurodegeneration. This means that drugs that failed in clinical trials for cancer may provide a new therapeutic opportunity for Alzheimer’s disease.”
Researchers observed that when mice are lacking the PKCα gene, their neurons function normally, even in the presence of amyloid beta. After restoration of PKCα, amyloid beta caused neuronal damage, leading researchers to believe that the protein only causes damage when the enzyme is active. Moreover, the team looked into a database of genetic information for 1,345 people in 410 families with late-onset Alzheimer’s disease, and identified three variants of PKCα that were associated with the disease in five families. When researchers replicated these variants in cell lines, PKCα activity was increased.
Researchers believe there are possibly many other factors that can increase the enzyme’s activity, and other still unknown genetic mutations that increase the likelihood of developing Alzheimer’s.
“Next we want to identify more molecules participating in the pathophysiology,” said Dr. Roberto Malinow, the study’s senior author. “The more steps in the mechanism we can understand, the more therapeutic targets we’ll find for Alzheimer’s disease.”
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