Small Molecule Restores Protein Synthesis and Improves Memory and Cognitive Function in Alzheimer’s Disease Mice

Small Molecule Restores Protein Synthesis and Improves Memory and Cognitive Function in Alzheimer’s Disease Mice

Scientists have found an experimental small molecule is effective at restoring protein synthesis in the neurons of Alzheimer’s disease mice and helped to restore memory and improve cognitive function.

Alzheimer’s disease is the most common form of dementia and affects more than 35 million people worldwide. Characteristics of the disease include the build up of amyloid-β (Aβ) peptide in the brain, the formation of neurofibrillary tangles, loss of synapses, neurodegeneration, memory loss, and loss of cognitive function. There is currently no cure for Alzheimer’s disease, but treatments can help to reduce neuroinflammation and slow the formation of amyloid plaques.

One feature of the disease that has been shown to contribute to memory deficits is impaired protein synthesis. An international team of researchers explored whether boosting protein synthesis in neurons could hold back or reverse the loss of cognitive function.

“We and others have previously shown that impairments in brain protein synthesis contribute memory deficits in Alzheimer’s disease model mice, and that the brains of Alzheimer’s patients exhibit clear signs of impaired protein synthesis,” said Sergio Ferreira, PhD, professor at the Institute of Biophysics at Brazil’s Federal University of Rio de Janeiro (UFRJ), and co-senior author of the study. “We thus asked ourselves whether rescuing brain protein synthesis might be an approach to improve memory function in Alzheimer’s disease.”

The researchers concentrated on a synthetic small molecule called ISRIB, which had previously been shown to boost protein synthesis. ISRIB is an ISR inhibitor that targets translation initiation and stimulates cellular protein synthesis. The researchers investigated whether ISRIB was effective at restoring synaptic plasticity and hippocampal functions and cognition in mice with Alzheimer’s like symptoms.

In a mouse model of Alzheimer’s disease, the researchers tested the effectiveness of ISRIB and assessed the results using well established memory tests, such as navigation of a maze.  The researchers found that after treatment with ISRIB, memory function in the mice improved and protein synthesis in the hippocampus was restored.

“This work is the first to show that reversing impaired protein synthesis in brains afflicted by Alzheimer’s disease through a pharmacological approach is not only feasible, but also effective,” said Mauricio Martins-Oliveira, PhD, a postdoctoral researcher at New York University’s Center for Neural Science, and first author of the study.

“Our findings show that jump-starting protein synthesis in the brain can revive lost cognitive functions. We hope that this work can serve as a step forward in treating this devastating disease,” said Eric Klann, PhD, a professor in NYU’s Center for Neural Science and senior co-author of the study.

You can read more about the study in the paper – Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease – which was recently published in Science Signaling. DOI: 10.1126/scisignal.abc5429