PMID- 29576474 OWN - NLM STAT- MEDLINE DCOM- 20190919 LR - 20210109 IS - 1879-0445 (Electronic) IS - 0960-9822 (Print) IS - 0960-9822 (Linking) VI - 28 IP - 7 DP - 2018 Apr 2 TI - The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. PG - 1079-1089.e4 LID - S0960-9822(18)30232-X [pii] LID - 10.1016/j.cub.2018.02.047 [doi] AB - Cognitive disabilities that occur with age represent a growing and expensive health problem. Age-associated memory deficits are observed across many species, but the underlying molecular mechanisms remain to be fully identified. Here, we report elevations in the levels and activity of the striatal-enriched phosphatase (STEP) in the hippocampus of aged memory-impaired mice and rats, in aged rhesus monkeys, and in people diagnosed with amnestic mild cognitive impairment (aMCI). The accumulation of STEP with aging is related to dysfunction of the ubiquitin-proteasome system that normally leads to the degradation of STEP. Higher level of active STEP is linked to enhanced dephosphorylation of its substrates GluN2B and ERK1/2, CREB inactivation, and a decrease in total levels of GluN2B and brain-derived neurotrophic factor (BDNF). These molecular events are reversed in aged STEP knockout and heterozygous mice, which perform similarly to young control mice in the Morris water maze (MWM) and Y-maze tasks. In addition, administration of the STEP inhibitor TC-2153 to old rats significantly improved performance in a delayed alternation T-maze memory task. In contrast, viral-mediated STEP overexpression in the hippocampus is sufficient to induce memory impairment in the MWM and Y-maze tests, and these cognitive deficits are reversed by STEP inhibition. In old LOU/C/Jall rats, a model of healthy aging with preserved memory capacities, levels of STEP and GluN2B are stable, and phosphorylation of GluN2B and ERK1/2 is unaltered. Altogether, these data suggest that elevated levels of STEP that appear with advancing age in several species contribute to the cognitive declines associated with aging. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Castonguay, David AU - Castonguay D AD - Department of Pharmacology and Physiology, Universite de Montreal, and Hopital du Sacre-Coeur de Montreal Research Center, Montreal, QC, Canada. FAU - Dufort-Gervais, Julien AU - Dufort-Gervais J AD - Department of Pharmacology and Physiology, Universite de Montreal, and Hopital du Sacre-Coeur de Montreal Research Center, Montreal, QC, Canada. FAU - Menard, Caroline AU - Menard C AD - Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada; Department of Medecine, Universite de Montreal, Centre Hospitalier de l'Universite de Montreal Research Center, Montreal, QC, Canada. FAU - Chatterjee, Manavi AU - Chatterjee M AD - Child Study Center, Yale University School of Medicine, New Haven, CT, USA. FAU - Quirion, Remi AU - Quirion R AD - Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada. FAU - Bontempi, Bruno AU - Bontempi B AD - Universite de Bordeaux, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodegeneratives, UMR 5293, Bordeaux, France. FAU - Schneider, Jay S AU - Schneider JS AD - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA. FAU - Arnsten, Amy F T AU - Arnsten AFT AD - Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. FAU - Nairn, Angus C AU - Nairn AC AD - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. FAU - Norris, Christopher M AU - Norris CM AD - Department of Molecular and Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. FAU - Ferland, Guylaine AU - Ferland G AD - Department of Nutrition, Universite de Montreal, and Institut de Cardiologie de Montreal, Montreal, QC, Canada. FAU - Bezard, Erwan AU - Bezard E AD - Universite de Bordeaux, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodegeneratives, UMR 5293, Bordeaux, France. FAU - Gaudreau, Pierrette AU - Gaudreau P AD - Department of Medecine, Universite de Montreal, Centre Hospitalier de l'Universite de Montreal Research Center, Montreal, QC, Canada. FAU - Lombroso, Paul J AU - Lombroso PJ AD - Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Child Study Center, Yale University School of Medicine, New Haven, CT, USA. Electronic address: paul.lombroso@yale.edu. FAU - Brouillette, Jonathan AU - Brouillette J AD - Department of Pharmacology and Physiology, Universite de Montreal, and Hopital du Sacre-Coeur de Montreal Research Center, Montreal, QC, Canada; Child Study Center, Yale University School of Medicine, New Haven, CT, USA. Electronic address: jonathan.brouillette@umontreal.ca. LA - eng GR - R01 AG027297/AG/NIA NIH HHS/United States GR - RF1 AG027297/AG/NIA NIH HHS/United States GR - P50 AG047270/AG/NIA NIH HHS/United States GR - K01 AG024190/AG/NIA NIH HHS/United States GR - P30 AG028383/AG/NIA NIH HHS/United States GR - R01 MH052711/MH/NIMH NIH HHS/United States GR - R01 MH091037/MH/NIMH NIH HHS/United States GR - CIHR/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180322 PL - England TA - Curr Biol JT - Current biology : CB JID - 9107782 RN - 42HK56048U (Tyrosine) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor) SB - IM MH - Aged, 80 and over MH - Animals MH - Case-Control Studies MH - Female MH - Hippocampus/*metabolism MH - Humans MH - Macaca mulatta MH - Male MH - Memory Disorders/*physiopathology MH - Mice MH - Mice, Inbred C57BL MH - Phosphorylation MH - Protein Tyrosine Phosphatases, Non-Receptor/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Tyrosine/*metabolism PMC - PMC5901906 MID - NIHMS954569 OTO - NOTNLM OT - aging OT - animal behaviors OT - animal models OT - hippocampus OT - memory OT - phosphatase STEP EDAT- 2018/03/27 06:00 MHDA- 2019/09/20 06:00 PMCR- 2019/04/02 CRDT- 2018/03/27 06:00 PHST- 2017/09/27 00:00 [received] PHST- 2017/12/27 00:00 [revised] PHST- 2018/02/19 00:00 [accepted] PHST- 2018/03/27 06:00 [pubmed] PHST- 2019/09/20 06:00 [medline] PHST- 2018/03/27 06:00 [entrez] PHST- 2019/04/02 00:00 [pmc-release] AID - S0960-9822(18)30232-X [pii] AID - 10.1016/j.cub.2018.02.047 [doi] PST - ppublish SO - Curr Biol. 2018 Apr 2;28(7):1079-1089.e4. doi: 10.1016/j.cub.2018.02.047. Epub 2018 Mar 22.