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

David Castonguay, Julien Dufort-Gervais, Caroline Ménard, Manavi Chatterjee, Rémi Quirion, Bruno Bontempi, Jay S. Schneider, Amy F.T. Arnsten, Angus C. Nairn, Christopher M. Norris, Guylaine Ferland, Erwan Bézard, Pierrette Gaudreau, Paul J. Lombroso, Jonathan Brouillette
Current Biology. 2018-04-01; 28(7): 1079-1089.e4
DOI: 10.1016/j.cub.2018.02.047

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1. 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.

Castonguay D(1), Dufort-Gervais J(1), Ménard C(2), Chatterjee M(3), Quirion R(4),
Bontempi B(5), Schneider JS(6), Arnsten AFT(7), Nairn AC(8), Norris CM(9),
Ferland G(10), Bézard E(5), Gaudreau P(11), Lombroso PJ(12), Brouillette J(13).

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: .
(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: .

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.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.cub.2018.02.047
PMCID: PMC5901906 [Available on 2019-04-02]
PMID: 29576474

Auteurs Bordeaux Neurocampus