Small molecule cognitive enhancer reverses age-related memory decline in mice
Authors: Morgane Boone
Amber Nolan
Susanna Rosi
Luz Delgado
Maria-Serena Paladini
Edward Elizarraras
Karen Krukowski
Gonzalo Ureta
Katherine Grue
Elma S Frias
Peter Walter
Sebastian Bernales
Journal: eLife (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: ISR; aging; immune dysfunction; memory; mouse
Affiliations: 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 Pathology, University of California at San Francisco, San Francisco, United States, Biochemistry and Biophysics, University of California at San Francisco, San Francisco, United States, Fundación Ciencia & Vida, Santiago, Chile, Howard Hughes Medical Institute, 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

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. 

Retracted: No

PubPeer comments:
  BALB c mice (50) applied in the present research were bought from Tianjin University (Tianjin, China). All of the animals utilized in the experiment were seeded at 20u201325 u0004C standard conditions, with free water and food. Then, the EV71 virus was multiplied in 293T cells and collected for infection; 10^9 PFU EV71 virus were **fed to the mice** for the HFMD animal model construction The age of the mice is not considered important. Infecting BALB c mice with EV71 virus requires 1-week-old mice, a mouse-adapted virus strain, and intra-peritoneal injection. Feeding doesn t work. This experiment never happened. -----------------------  Due to their structures and topology, as well as their wide latent application in drug delivery, separation, gas storage, sensing, and catalysis, [coordination polymers] have developed into a significant class of compounds [5u201310]. - [8] D. Zhang, M.M. Wang, N. Jiang, Y. Liu, X.N. Yu, H.B. Zhang. Int. J. Electrochem. Sci., 15, 4117(2020). ** Electrochemical Corrosion Behavior of Ni-doped ZnO Thin Film Coated on Low Carbon Steel Substrate in 3.5% NaCl Solution ** - [9] H. Du, C. Ma, W. Ma, H. Wang. Process. Appl. Ceram., 12, 303 (2018) ** ) Microstructure Evolution and Dielectric Properties of Ce-doped SrBi4Ti4O15 Ceramics Synthesized via Glycine-nitrate Process ** [9] and [10] have nothing to do with coordination polymers. On the other hand, they do appear together (in equally irrelevant contexts) in the References of scores of papers from the same production line. ,