When Brain Regions Can’t Communicate, and How to Prevent It

Inhibiting the activity of an enzyme in the brain may improve brainwave function in people with neurological diseases such as Alzheimer’s disease and schizophrenia, researchers in the Department of Molecular and Cellular Biology have found.

Brainwaves – also known as neuronal oscillations – are created by the electrical impulses generated by groups of brain cells.  These oscillations are critical for communication among brain cells both within and between different regions of the brain, and occur at different frequencies, depending on what activity the brain is doing. 

“Patients with cognitive decline have abnormal oscillations, but it is not always clear what causes these abnormalities,” says Prof. Melissa Perreault, who led the study. “In Alzheimer’s disease, we have a pretty good idea of what contributes to wave frequency deficits - they are linked to deposits of a protein called tau that cause physical changes to the brain.  But we don’t know how cognitive processes are altered in other disorders.”

She and colleagues at the University of Toronto have now found a likely culprit: an enzyme called glycogen synthase kinase-3, or GSK-3. This particular enzyme is overactive in Alzheimer’s disease, adding extra phosphate groups to the protein tau, which is what causes it to aggregate into deposits. By blocking the activity of this enzyme in healthy rats, Perreault and her collaborators were able to improve spatial memory and increase brainwave function, demonstrating a mechanism by which GSK-3 can also affect brainwave function directly.

Professor Melissa Perreault

“Nobody has yet investigated a direct mechanistic link between GSK-3 and neuronal oscillatory dysfunction, and here we lay the groundwork that shows this connection,” says Perreault.

The rats were treated with SB 216763, a compound that inhibits GSK-3, and compared to a control group. Spatial memory was measured using a maze test, and the impacts on neuronal oscillations evaluated. Rats that were given the GSK-3 specific inhibitor performed consistently better in aspects of memory and brain function than rats in the control group.

The results not only provide more information about the role of GSK-3 in Alzheimer’s disease, but how it can alter cognitive processes in other neural disorders as well.

“We believe GSK-3 is a convergence point in any number of disorders of cognitive decline, in terms of its importance in the regulation of neuronal oscillatory activity, a process critical to brain systems communication. Our current goal is to continue to explore the role of GSK-3 in the context of schizophrenia,” says Perreault.

The importance of GSK-3 as a potential “master regulator” of neurological decline opens up the exciting possibility of targeting the enzyme to treat or prevent a range of neurological disorders.  But this will be no easy task, warns Perreault. GSK-3 also plays a role in cell death signaling and if it is inhibited, excessive cell growth could ensue, which is one way that cancer can form. 

While such a treatment may be a long way off, the study marks an important step towards understanding how we might someday prevent the brain changes associated with cognitive disorders.

This research was completed in collaboration with Tuan Nguyen, Theresa Fan and Susan R. George, University of Toronto. Funding was provided by a grant from the W. Garfield Weston Foundation.

Read the full article in the journal Frontiers in Aging Neuroscience.

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