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Enzyme Drives Cognitive Decline in Mice, Provides New Target for Alzheimer’s - Neuroscience News
Nov 29, 2022 2 mins, 3 secs
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Summary: A subtle increase of the PKCα protein produces biochemical, cellular, and cognitive impairments akin to those seen in Alzheimer’s disease.

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).

The M489V mutation has since been shown to increase the activity of PKCα 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 University of California San Diego School of Medicine found that the subtle increase in PKCα was sufficient to produce biochemical, cellular and cognitive impairments in mice, similar to those observed in human AD.

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 the next year and a half (corresponding to approximately 55 years in human aging).

“We were surprised to find that just a slight increase in PKCα activity was enough to recreate the Alzheimer’s phenotype in a mouse,” said senior author Alexandra C.

Furthermore, phosphorylation of a known PKCα substrate was increased by approximately four-fold in these brains, 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,” said Newton.

“Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model” by Gema Lordén et al.

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

Exquisitely tuned activity of protein kinase C (PKC) isozymes is essential to maintaining cellular homeostasis

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 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 biochemical, cellular, and ultimately cognitive effects observed

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

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