SAN DIEGO—The main culprit of Alzheimer's disease is known to be amyloid beta, which forms plaques within the brain that, combined with neurofibrillary tangles, characterize the neurodegenerative disease. Recently, however, a team of researchers from the University of California, San Diego School of Medicine and Harvard Medical School have found another guilty party behind amyloid beta: the enzyme Protein Kinase C (PKC) alpha, which is necessary for amyloid beta to damage neuronal connections. In addition, they also pinpointed genetic variations that were found to enhance PKC alpha activity in Alzheimer’s patients.
The research consisted of a collaboration led by Dr. Alexandra Newton, professor of pharmacology at UC San Diego School of Medicine; Dr. Roberto Nalinow, Distinguished Professor of Neurosciences and Neurobiology and holder of the Shiley-Marcos Endowed Chair in Alzheimer's Disease in Honor of Dr. Leon Thal at UC San Diego School of Medicine; and Dr. Rudolph Tanzi, professor of neurology at Harvard Medical School, who are experts in PKC, neuroscience and genomics, respectively.
The research was conducted in mouse models, and Manilow's team discovered that when the PKC alpha gene is missing, neurons function normally, even in the presence of amyloid beta. When PKC alpha was restored, amyloid beta again impaired neuronal function.
“Until recently, it was thought that PKC helped cells survive, and that too much PKC activity led to cancer. Based on that assumption, many companies tested PKC inhibitors as drugs to treat cancer, but they didn’t work,” said Newton. “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. 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.”
Tanzi's team applied their database, which consists of genetic information acquired via whole-genome sequencing of 1,345 people in 410 families with late-onset Alzheimer's disease, in a search for rare genetic mutations found only in family members with Alzheimer's. As a result, they pinpointed three variants in one form of the PKC enzyme, PKC alpha that were associated with Alzheimer's disease in five families. When these three gene variants were replicated in laboratory cell lines, PKC alpha activity was increased in each line.
Specifically, as noted in the study's abstract, “Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the Aβ precursor CT100 revealed that PKCα was required for the reduced synaptic activity caused by Aβ. In PRKCA(-/-) neurons expressing CT100, introduction of PKCα, but not PKCα lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKCα to the synapse is required for its mediation of the effects of Aβ. Thus, enhanced PKCα activity may contribute to AD, possibly by mediating the actions of Aβ on synapses.”
According to Newton, there are several ways to influence the activity of PKC alpha, and she expects there could be a number of other inherited genetic variations that can indirectly boost or inhibit PKC activity.
Manilow noted in a press release that their next step with this work will be the identification of more molecules that play a role in the pathophysiology of Alzheimer's.
The paper detailing these findings, titled “Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease,” was published in Science Signaling.
