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ISRIB, a small molecule cognitive enhancer, reverses age-related memory decline in mice.

Memory dysfunction is a commonly occurring symptom of neurological injury and disease, including traumatic brain injury (TBI). Because memory dysfunction can be distressing and debilitating, researchers are working to understand the cellular mechanisms that cause it and to develop promising treatment options to restore full cognitive function in people with TBI and other neurological disorders.

A research team at the University of California at San Francisco recently published a study in which they examined the ability of a drug called ISRIB to improve the performance of aging mice in memory-related tasks. ISRIB works by targeting the integrated stress response (ISR), a cellular mechanism that is activated in neurodegenerative diseases or in circumstances of neurological dysfunction. The natural aging process causes errors during cellular protein synthesis. To mitigate the accumulation of incorrectly formed proteins, the ISR is activated to reduce protein synthesis altogether—which is well known to negatively impact memory formation. ISRIB halts this process early by inhibiting the ISR from blocking protein synthesis. Additionally, ISRIB is thought to reduce the body’s immune response in the brain, thereby targeting other types of cognitive dysfunction that are caused by over-activation of the immune response.

To study the impact of ISRIB on age-related memory decline, the researchers administered ISRIB by injection for three days in a row and measured level of proteins that are known to increase in the brain during aging. They found that the mice treated with ISRIB had lower levels of this protein than control mice who received no treatment, and similar levels to young mice. Notably, this effect was seen 18 days after treatment, suggesting that ISRIB has long-lasting effects.

Next, the researchers determined whether ISRIB could cause behavioral improvements in spatial learning and memory. They trained young and old mice to locate an underwater platform and recorded the number of mistakes they made before finding the platform. As expected, young mice made fewer mistakes than older mice. However, when older mice were treated with ISRIB prior to training, they made fewer mistakes than older mice who did not receive treatment. As the animals only received ISRIB treatment at the start of the two-day training period, this result is important because it demonstrates that ISRIB acts quickly to improve spatial learning and memory. They also found that the effect of ISRIB was long lasting: when they tested the impact of ISRIB on working memory (memory that is needed to use cues from their environment to complete a changing task), they found that ISRIB was effective at improving performance in older mice 18 days after the drug was administered.

Last, the researchers looked at the way that ISRIB altered brain function at a cellular level. They studied the structure and function of neurons in older mice who had been treated with a single injection of ISRIB. They found that the neurons from mice who had been treated with ISRIB were more similar to those of young mice than they were to older mice who did not receive treatment. Consistent with their prediction that ISRIB reduces the immune response and the ISR, they also saw ISRIB mice had decreased markers of inflammation and ISR activation.

This study built upon previous research from this group which showed that ISRIB could reduce memory and cognitive deficits following mild traumatic brain injury. The fact that the researchers found improvements in both populations suggests that memory decline from TBI may be caused by similar mechanisms as age-related memory decline. The study provides clear evidence for the involvement of the ISR in age-related memory decline, and the findings are important both for our understanding and treatment of neurological deficits. The ability of ISRIB to restore memory decline suggests that memory deficits are not caused by permanent damage, but by activation of a cellular pathway that can be targeted and reversed with medication. Further research can help to understand when and how ISRIB can be used to treat cognitive deficits due to brain injury or disease, and to better understand the types of neurological dysfunction that ISRIB can help treat.

Krukowski K, Nolan A, Frias ES, et al. Small molecule cognitive enhancer, reverses age-related memory decline in mice. bioRxiv. (2020).

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