Enzyme Drives Cognitive Decline in Mice, Provides New Target for Alzheimer’s

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Overview: A subtle increase in the PKCα protein causes biochemical, cellular and cognitive impairments similar to those seen in Alzheimer’s disease. The finding offers a potential new target for treating the neurodegenerative disorder.

Source: UCSD

In a recent search for gene variants associated with Alzheimer’s disease (AD), several affected families showed a mutation in an enzyme called protein kinase C-alpha (PKCα). Family members with this mutation had AD; those without the mutation do not.

The M489V mutation has since been shown to increase PKCα activity by a modest 30 percent, so whether and how it contributes to the neuropathology of AD has remained unclear.

In a new study, researchers at the University of California San Diego School of Medicine found that the subtle increase in PKCα was enough to cause biochemical, cellular and cognitive impairment in mice similar to that seen in AD in humans.

The findings, published online Nov. 23, 2022 in Nature communicationposition PKCα as a promising therapeutic target for the disease.

PKCα regulates the function of many other proteins, especially in the brain.

The enzyme facilitates chemical reactions that add phosphate groups to other proteins, shaping their activity and ability to bind to other molecules. By tuning 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 AD, several research teams collaborated to first generate a mouse model with the PKCα M489V mutation and then assess its biochemistry and behavior over a year and a half (equivalent to approximately 55 years in human aging).

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 neuronal proteins were misregulated.

After 4.5 months, the mice’s hippocampal neurons showed several cellular changes, including synaptic depression and decreased density of dendritic spines.

After 12 months, the mice showed decreased performance in behavioral tests of spatial learning and memory, clear evidence of cognitive decline.

“We were surprised to find that just a small increase in PKCα activity was enough to mimic the Alzheimer’s phenotype in a mouse,” said senior author Alexandra C. Newton, Ph.D., Distinguished Professor of Pharmacology at the UC San Diego School of Medicine.

“This is a great example of the importance of homeostasis in biology – even small adjustments in kinase activity can lead to pathology if the effects are allowed to accumulate over a lifetime.”

To confirm whether similar enzymatic changes could be observed in human patients, the researchers also measured protein levels in the frontal cortex of human brains of deceased patients with AD and control subjects.

Compared to wild-type control mice, hippocampal neurons in PKCa M489V mice showed fewer dendritic spines. Credit: UC San Diego Health Sciences

Brains of AD patients showed a 20 percent increase in PKCα. In addition, phosphorylation of a known PKCα substrate was increased about 4-fold in this brain, further suggesting that PKCα activity was enhanced in the human AD brain.

“The PKCα M489V mutation has been a great way to test the role of this enzyme in AD, but there are many other ways to have aberrant PKCα,” Newton said.

“We are discovering that many mutations associated with AD are in genes that regulate PKCα, so a variety of gene variants may in fact converge on the same major pathway.”

The authors note that several pharmacological inhibitors of PKCα have already been developed for use in cancer and could be reused to treat AD. Future drug development could 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 another earlier process happening in the brain,” said Newton.

“Our findings add to a growing body of evidence that PKCα may be an important part of that 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 of 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 news about Alzheimer’s disease

Author: Scott LaFee
Source: UCSD
Contact: Scott LaFee–UCSD
Image: The image is credited to UCSD

Original research: Open access.
“Enhanced activity of the Alzheimer’s disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model” by Gema Lordén et al. Nature communication


Abstract

Enhanced activity of the Alzheimer’s disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model

Finely tuned activity of protein kinase C (PKC) isozymes is essential for maintaining cellular homeostasis. While loss-of-function mutations are generally associated with cancer, gain-of-function variants in one isoenzyme, PKCα, are associated with Alzheimer’s disease (AD).

Here we show that the increased activity of one variant, PKCα M489V, is sufficient to rewire the brain’s phosphoproteome, drive synaptic degeneration and impair cognition in a mouse model.

This variant causes a modest 30% increase in catalytic activity without altering on/off activation dynamics or stability, underscoring that enhanced catalytic activity is sufficient to drive the observed biochemical, cellular, and ultimately cognitive effects.

Analysis of hippocampal neurons from PKCα M489V mice reveals enhanced amyloid-β-induced synaptic depression and reduced spine density compared to wild-type mice.

Behavioral studies show that this mutation alone is enough to affect cognition and, when linked to a mouse model of AD, further accelerates cognitive decline.

The drugability of protein kinases positions PKCα as a promising therapeutic target in AD.

The Valley Voice
The Valley Voicehttp://thevalleyvoice.org
Christopher Brito is a social media producer and trending writer for The Valley Voice, with a focus on sports and stories related to race and culture.

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