Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, San Francisco, United States; Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States
Amber Nolan
Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States; Department of Pathology, University of California at San Francisco, San Francisco, United States
Elma S Frias
Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, San Francisco, United States; Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States
Biochemistry and Biophysics, University of California at San Francisco, San Francisco, United States
Gonzalo Ureta
Fundación Ciencia & Vida, Santiago, Chile
Katherine Grue
Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, San Francisco, United States; Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States
Maria-Serena Paladini
Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, San Francisco, United States; Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States
Edward Elizarraras
Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, San Francisco, United States; Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States
Biochemistry and Biophysics, University of California at San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, United States
Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, San Francisco, United States; Brain and Spinal Injury Center, University of California at San Francisco, San Francisco, United States; Department of Neurological Surgery, University of California at San Francisco, San Francisco, United States; Weill Institute for Neuroscience, University of California at San Francisco, San Francisco, United States; Kavli Institute of Fundamental Neuroscience, University of California at San Francisco, San Francisco, United States
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.
