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

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

Curr Biol

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:

Published: April 2018

AI Article Synopsis

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901906PMC
http://dx.doi.org/10.1016/j.cub.2018.02.047DOI Listing

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