Overview: Small increases in PKCα protein cause biochemical, cellular, and cognitive deficits similar to those seen in Alzheimer’s disease. This discovery provides a potential new target for the treatment of neurodegenerative diseases.
A recent search for genetic variants associated with Alzheimer’s disease (AD) showed that several affected families showed mutations in an enzyme called protein kinase C-alpha (PKCα). A family member with this mutation had Alzheimer’s disease. Mutation-free ones did not.
Since the M489V mutation has since been shown to increase the activity of PKCα by only 30%, it remains unclear whether and how it contributes to AD neuropathology.
In a new study, researchers at the University of California, San Diego School of Medicine, found that a small increase in PKCα was sufficient to cause biochemical, cellular and cognitive deficits in mice similar to those observed in human AD. I discovered something.
The survey results were published online on November 23, 2022. Nature Communicationspositioning PKCα as a promising therapeutic target in this disease.
PKCα regulates the function of many other proteins, especially in the brain.
This enzyme facilitates chemical reactions that add phosphate groups to other proteins, forming their activity and ability to bind to other molecules. By modulating the phosphorylation state of proteins in the synaptic environment, PKCα may play an important role in synaptic function and neuronal signaling.
To assess its role in Alzheimer’s disease, several research teams collaborated to first create a mouse model with the PKCα M489V mutation and then assess its biochemistry and behavior over the next year and a half (human equivalent to about 55 years of aging).
After 3 months, the brains of mutant mice had significantly altered levels of protein phosphorylation compared to the brains of wild-type control mice, indicating that neuronal proteins are misregulated.
By 4.5 months, mouse hippocampal neurons exhibited several cellular changes, including synaptic inhibition and reduced density of dendritic spines.
By 12 months, mice showed decreased performance on behavioral tests of spatial learning and memory. This is clear evidence of cognitive decline.
“We were surprised to find that even a modest increase in PKCα activity was sufficient to recapitulate the Alzheimer’s disease phenotype in mice,” said senior author Alexandra C. Newton, PhD. .
“This is a striking example of the importance of homeostasis in biology. I have.”
To see if similar enzymatic changes could be observed in human patients, the researchers also measured protein levels in the human brain frontal cortex of deceased patients with Alzheimer’s disease and controls.
There was a 20% increase in PKCα in the brains of AD patients. Moreover, phosphorylation of known PKCα substrates was increased ~4-fold in these brains, further suggesting that PKCα activity was enhanced in human AD brains.
“The PKCα M489V mutation was a great way to test the role of this enzyme in Alzheimer’s disease, but there are many other ways to have aberrant PKCα,” Newton said.
“We found that many mutations associated with Alzheimer’s disease are in genes that regulate PKCα, so it is possible that different genetic variants are indeed converging on this same important pathway.”
The authors note that several pharmacological inhibitors of PKCα have already been developed for use in cancer and may be repurposed for the treatment of AD. Future drug development may focus on ways to selectively inhibit PKCα at synapses.
“It’s becoming increasingly clear that the amyloid plaques seen in Alzheimer’s disease are secondary to other early processes occurring in the brain,” Newton said.
“Our findings add to growing evidence that PKCα may be an important part of that process and may be a promising target for the treatment or prevention of Alzheimer’s disease.”
Co-authors include Gema Lorden, Jacob M. Wozniak, Kim Dore, Laura E. Dozier, Gentry N. Patrick, and David J. Gonzalez from the University of California, San Diego. Amanda J. Roberts and Chelsea Cates-Gatto of the Scripps Research Institute. Rudolf E. Tanzi of Harvard Medical School.
About this Alzheimer’s Disease Research News
author: Scott Laffey
contact: Scott Laffey – UCSD
image: Images credited to UCSD
Original research: open access.
“Enhanced activity of an Alzheimer’s disease-associated variant of protein kinase Cα promotes cognitive decline in a mouse model” Gema Lordén et al. Nature Communications
Enhanced activity of an Alzheimer’s disease-associated variant of protein kinase Cα promotes cognitive decline in a mouse model
The finely regulated activity of protein kinase C (PKC) isoenzymes is essential for maintaining cellular homeostasis. Loss-of-function mutations are commonly associated with cancer, whereas gain-of-function variants of one isoenzyme, PKCα, are associated with Alzheimer’s disease (AD).
Here we show that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, promote synaptic degeneration and impair cognition in a mouse model.
This variant increases catalytic activity by only 30% without altering activation on/off dynamics or stability. This highlights that enhanced catalytic activity is sufficient to drive the observed biochemical, cellular and ultimately cognitive effects.
Analysis of hippocampal neurons from PKCαM489V mice reveals enhanced synaptic inhibition and reduced spine density induced by amyloid-β compared with wild-type mice.
Behavioral studies reveal that this mutation alone is sufficient to impair cognition, and when combined with mouse models of AD, further accelerates cognitive decline.
The druggability of protein kinases positions PKCα as a promising therapeutic target in AD.