Summary: Subtle increases in PKCα protein cause biochemical, cellular, and cognitive impairments similar to those seen in Alzheimer’s disease. These findings provide potential new targets for the treatment of neurodegenerative disorders.
In a recent search for gene variants associated with Alzheimer’s disease (AD), several affected families showed mutations in an enzyme called protein kinase C-alpha (PKCα). Family members with this mutation have AD; those without mutations do not.
The M489V mutation has now been shown to increase PKCα activity by 30 percent, so whether and how it contributes to AD neuropathology remains unclear.
In a recent study, researchers at the University of California San Diego School of Medicine found that subtle increases in PKCα are sufficient to produce biochemical, cellular and cognitive impairments in mice, similar to those observed in human AD.
The findings, published online on November 23, 2022 at Natural Communicationpositioning PKCα as a promising therapeutic target for these diseases.
PKCα regulates the function of many other proteins, especially in the brain.
These enzymes facilitate chemical reactions that add phosphate groups to other proteins, forming their activity and ability to bind to other molecules. By adjusting the phosphorylation status of proteins in the synaptic environment, PKCα may play an important role in synaptic function and neuronal signaling.
To assess its role in AD, several research teams collaborated to generate a mouse model with the PKCα M489V mutation and then assess its biochemistry and behavior over the next half year (corresponding to a human lifespan of 55 years).
After three months, the brains of the mutated mice had significantly altered levels of protein phosphorylation compared to the brains of wild-type control mice, indicating that the neuronal protein was misfolded.
At 4.5 months, rat hippocampal neurons showed several cellular changes, including synaptic depression and reduced density of dendritic spines.
By 12 months, the mice showed poor performance in behavioral tests of spatial learning and memory, clear evidence of cognitive decline.
“We were surprised that simply increasing PKCα activity was sufficient to recreate the Alzheimer’s phenotype in mice,” said senior author Alexandra C. Newton, Ph.D., Distinguished Professor of Pharmacology at the UC San Diego School of Medicine. .
“This is a striking example of the importance of homeostasis in biology—even small tweaks in kinase activity can lead to pathology if the effects are allowed to accumulate over a lifetime.”
To confirm that similar enzymatic changes can be observed in human patients, the researchers also measured protein levels in the frontal cortex of human brains from patients who had died with AD and control individuals.
Brains from AD patients showed a 20 percent increase in PKCα. Furthermore, phosphorylation of known PKCα substrates increased approximately fourfold in these brains, further indicating that PKCα activity is enhanced in human AD brains.
“The PKCα M489V mutation has been a good way to test the role of this enzyme in AD, but there are many other ways to have aberrant PKCα,” Newton said.
“We found that many of the mutations associated with AD are in genes that regulate PKCα, so different gene variants may converge to the same important pathway.”
The authors note that several pharmacological inhibitors of PKCα have been developed for use in cancer and may be used to treat AD. Future drug development may focus on ways to selectively inhibit PKCα at the synapse.
“It’s becoming increasingly clear that the amyloid plaques we see in AD are secondary to some other process going on in the brain,” Newton said.
“Our findings add to the growing body of evidence that PKCα may be an important part of this process, and is a promising target for treating or preventing Alzheimer’s disease.”
Co-authors include: Gema Lorden, Jacob M. Wozniak, Kim Dore, Laura E. Dozier, Gentry N. Patrick and David J. Gonzalez, all at UC San Diego; Amanda J. Roberts and Chelsea Cates-Gatto at The Scripps Research Institute; and Rudolph E. Tanzi at Harvard Medical School.
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About this Alzheimer’s disease research news
Author: Scott LaFee
Ignition: Scott LaFee – UCSD
Picture: The image is credited to UCSD
Original Research: Open access.
“Increased activity of the Alzheimer’s disease-associated protein kinase Cα variant leads to cognitive decline in a mouse model” by Gema Lordén et al. Natural Communication
Increased activity of the Alzheimer’s disease-associated protein kinase Cα variant causes cognitive decline in a mouse model
Excellent protein kinase C (PKC) isozyme activity is essential for maintaining cellular homeostasis. While loss-of-function mutations are commonly associated with cancer, gain-of-function variants in one isozyme, 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, drive synaptic degeneration, and impair cognition in a mouse model.
This variant resulted in a 30% increase in catalytic activity without altering activity dynamics or stability, suggesting that enhanced catalytic activity was sufficient to drive the observed biochemical, cellular, and cognitive effects.
Analysis of hippocampal neurons from PKCα M489V mice revealed amyloid-β-induced synaptic depression and reduced spine density compared to wild-type mice.
Behavioral studies show that this mutation alone is sufficient to impair cognition, and, when associated with a mouse model of AD, further accelerates cognitive decline.
The druggability of protein kinase positions PKCα as a promising therapeutic target in AD.