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.
Highlights
Inhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice
We previously discovered that interference with the drug-like small-molecule inhibitor rescued traumatic brain injury-induced behavioral and cognitive deficits [27,28,29], suggesting that this pharmacological tool may be useful in testing this notion
integrated stress response (ISR) activation leads to global reduction in protein synthesis and to translational upregulation of a select subset of mRNAs whose translation is controlled by small upstream open-reading frames in their 5’-UTRs [37, 38]
Summary
Inhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice. 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 agerelated brain phenotypes. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, interferon and T cell-mediated responses. Pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals. While often discussed in the context of disease, decreases in executive function as well as learning and memory decrements in older, healthy individuals are common (2, 3, 4 , 5). 83.7 million individuals above 65 years of age in the US; this represents a rapidly growing healthcare and economic concern [6]
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