Researchers from the University of California, San Francisco have discovered that a small molecule partially restores the cognitive abilities of mice suffering from age-related memory decline [1].
A response to damage
As the researchers explain, when neurons detect that something has gone wrong, either through the presence of misfolded proteins (amyloids) or traumatic brain injury, these cells cease to produce all the proteins they need for normal functioning. This mechanism is called the integrative stress response (ISR).
Under normal circumstances, the ISR is supposed to be a transitory, short-term response to stresses. However, as neurons age, these stresses accumulate, and the ISR begins to do more harm than good, preventing these cells from making the proteins they need to function. This prevents the formation of long-term memories, a fact that was discovered as far back as 1962 [2].
Hitting the reset button
In order to disrupt the ISR and restart the protein factories in neurons, the researchers of this study had previously developed an integrated stress response inhibitor (ISRIB), a small molecule that they had successfully tested on a mouse model of traumatic brain injury [3]. One protein that is upregulated in ISR is ATF4, a protein that ISRIB quickly diminishes, allowing for the formation of other, beneficial proteins.
ISRIB administration appears to have multiple beneficial results. For example, it beneficially affects how electricity flows in neurons, it restores mRNA expression to be more like that of young mice, and it partially restores the ability of brains to form memories even three weeks after administration, meaning that a single reset of the ISR has long-lasting effects.
Abstract
With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.
Conclusion
The ISR does not appear to be a direct cause of Alzheimer’s or other proteostasis diseases, it does not seem to be responsible for the failure of new brain cells to form (neurogenesis), and it is probably not responsible for all other sources of age-related cognitive decline. However, as this study shows, it plays an enormous role in the failure of aged brains to form new memories, and ISRIB may offer tremendous hope for elderly people who are attempting to learn new things.
Literature
[1] Krukowski, K., Nolan, A., Frias, E. S., Boone, M., Ureta, G., Grue, K., … & Walter, P. (2020). Small molecule cognitive enhancer reverses age-related memory decline in mice. bioRxiv.
[2] Flexner, J. B., Flexner, L. B., Stellar, E., Haba, G. D. L., & Roberts, R. B. (1962). Inhibition of protein synthesis in brain and learning and memory following puromycin. Journal of neurochemistry, 9(6), 595-605.
[3] Krukowski, K., Nolan, A., Frias, E. S., Grue, K., Becker, M., Ureta, G., … & Rosi, S. (2020). Integrated stress response inhibitor reverses sex-dependent behavioral and cell-specific deficits after mild repetitive head trauma. Journal of Neurotrauma, 37(11), 1370-1380.
