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Curr Biol. 2018 Apr 2;28(7):1079-1089.e4. doi: 10.1016/j.cub.2018.02.047. Epub 2018 Mar 22.

The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline.

Author information

1
Department of Pharmacology and Physiology, Université de Montréal, and Hôpital du Sacré-Coeur de Montréal Research Center, Montreal, QC, Canada.
2
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada; Department of Medecine, Université de Montréal, Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC, Canada.
3
Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
4
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
5
Université de Bordeaux, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
6
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
7
Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
8
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
9
Department of Molecular and Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
10
Department of Nutrition, Université de Montréal, and Institut de Cardiologie de Montréal, Montreal, QC, Canada.
11
Department of Medecine, Université de Montréal, Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC, Canada.
12
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.
13
Department of Pharmacology and Physiology, Université de Montréal, and Hôpital du Sacré-Coeur de Montréal Research Center, Montreal, QC, Canada; Child Study Center, Yale University School of Medicine, New Haven, CT, USA. Electronic address: jonathan.brouillette@umontreal.ca.

Abstract

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.

KEYWORDS:

aging; animal behaviors; animal models; hippocampus; memory; phosphatase STEP

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