Enzyme causes cognitive decline in mice and provides new target for Alzheimer's disease

Enzyme causes cognitive decline in mice and provides new target for Alzheimer’s disease

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

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

In a new study, researchers at the 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 seen in mice. human Alzheimer’s disease. The conclusions, published online on November 23, 2022 in Nature Communicationposition PKCα as a promising therapeutic target for the disease.

PKCα regulates the function of many other proteins, particularly 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 adjusting 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 the next year and a half (corresponding to approximately 55 years). in human aging).

After three months, the brains of the mutated mice showed significantly altered levels of protein phosphorylation compared to the brains of wild-type control mice, indicating that neuronal proteins were misregulated. At 4.5 months, the mice’s hippocampal neurons showed several cellular changes, including synaptic depression and reduced density of dendritic spines. At 12 months, the mice showed impaired performance in behavioral tests of spatial learning and memory, clear evidence of cognitive decline.

“We were surprised to find that a slight increase in PKCα activity was enough to recreate the Alzheimer’s phenotype in a mouse,” said lead author Alexandra C. Newton, PhD, professor emeritus of pharmacology at the faculty. of Medicine from UC San Diego. “This is an amazing example of the importance of homeostasis in biology – even minor changes 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 seen in human patients, the researchers also measured protein levels in the frontal cortex of human brains from deceased Alzheimer’s disease patients and control individuals. The brains of patients with Alzheimer’s disease showed a 20% increase in PKCα. Furthermore, phosphorylation of a known PKCα substrate was increased approximately four-fold in these brains, further suggesting that PKCα activity was enhanced in human AD brain.

“The PKCα M489V mutation was 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 find that many mutations associated with Alzheimer’s disease are in genes that regulate PKCα, so a variety of gene variants may in fact converge on this same important pathway.”

The authors note that several pharmacological inhibitors of PKCα have already been developed for use in cancer and could be repurposed to treat AD. Future drug development could focus on ways to selectively inhibit PKCα at the synapse.

“It is increasingly clear that the amyloid plaques we see in AD are secondary to another earlier process that occurs in the brain,” Newton said. “Our findings add to a growing body of evidence that PKCα may play an important role in this process and is 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, 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.

Funding for this study came, in part, from the Cure Alzheimer’s Fund, National Institutes of Health (grants R35GM122523 and NIHAG062429), and UC San Diego Graduate Education Programs (grants T32GM007752 and T32AR064194).

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