PT  - JOURNAL ARTICLE
AU  - Karen Krukowski
AU  - Amber Nolan
AU  - Elma S. Frias
AU  - Morgane Boone
AU  - Gonzalo Ureta
AU  - Katherine Grue
AU  - Maria-Serena Paladini
AU  - Edward Elizarraras
AU  - Luz Delgado
AU  - Sebastian Bernales
AU  - Peter Walter
AU  - Susanna Rosi
TI  - Small molecule cognitive enhancer reverses age-related memory decline in mice
AID  - 10.1101/2020.04.13.039677
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.13.039677
4099  - http://biorxiv.org/content/early/2020/04/15/2020.04.13.039677.short
4100  - http://biorxiv.org/content/early/2020/04/15/2020.04.13.039677.full
AB  - With increased life expectancy, age-associated cognitive decline becomes a growing concern. 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 activating transcription factor 4 (ATF4) protein levels. 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.ONE SENTENCE SUMMARY Inhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice.Competing Interest StatementSB is an employee of Praxis Biotech. SB, GU and LD work at Fundacion Ciencia & Vida and receive partial funding from Praxis Biotech. P.W. is an inventor on U.S. Patent 9708247 held by the Regents of the University of California that describes ISRIB and its analogs. Rights to the invention have been licensed by UCSF to Calico. P.W. is a consultant for Praxis Biotech LLC and Black Belt TX Limited. The authors declare no other competing interests.