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

doi:10.1016/j.cub.2018.02.047

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

Producción científica: Article › revisión exhaustiva

29 Citas (Scopus)

Resumen

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. The molecular changes leading to memory deficits during aging remain to be fully identified. Castonguay et al. provide genetic, behavioral, and molecular evidence that accumulation of the phosphatase STEP is a common molecular event that oppose synaptic strengthening and contributes to age-related memory deficits in mice, rats, monkeys, and humans.

Idioma original	English
Páginas (desde-hasta)	1079-1089.e4
Publicación	Current Biology
Volumen	28
N.º	7
DOI	https://doi.org/10.1016/j.cub.2018.02.047
Estado	Published - abr 2 2018

Nota bibliográfica

Publisher Copyright:
© 2018 Elsevier Ltd

Financiación

We thank laboratory members for helpful discussions and critical reading of the manuscript. We thank Jian Xu for providing the GST-GluN2B construct and Mitchell Powell for technical assistance. We thank Dr. Marilee Ogren for critical reading of the manuscript. Thank you also to Dr. Erin Abner at the Sanders-Brown Center on Aging for assistance with human case histories. This work was funded by a FRQS and Hôpital du Sacré-Coeur de Montréal (HSCM) grant (J.B.), NIH grants MH091037 and MH052711 (P.J.L.), AG047270 (A.C.N.), and AG024190 , AG027297 , and AG028383 , and Center’s ADC grant P30AG028383 (C.M.N.). This research was supported by an unrestricted grant from Motac Holding (J.S.S. and E.B.), and CNRS and ANR-10-MALZ-002 grants (B.B.). This project was funded by grants from the Canadian Institutes of Health Research (CIHR) (R.Q.) and the Quebec Network for Research on Aging (a network funded by Fonds de Recherche du Québec – Santé) (P.G. and G.F.). C.M. holds a postdoctoral fellowship from CIHR . We thank laboratory members for helpful discussions and critical reading of the manuscript. We thank Jian Xu for providing the GST-GluN2B construct and Mitchell Powell for technical assistance. We thank Dr. Marilee Ogren for critical reading of the manuscript. Thank you also to Dr. Erin Abner at the Sanders-Brown Center on Aging for assistance with human case histories. This work was funded by a FRQS and Hôpital du Sacré-Coeur de Montréal (HSCM) grant (J.B.), NIH grants MH091037 and MH052711 (P.J.L.), AG047270 (A.C.N.), and AG024190, AG027297, and AG028383, and Center's ADC grant P30AG028383 (C.M.N.). This research was supported by an unrestricted grant from Motac Holding (J.S.S. and E.B.), and CNRS and ANR-10-MALZ-002 grants (B.B.). This project was funded by grants from the Canadian Institutes of Health Research (CIHR) (R.Q.) and the Quebec Network for Research on Aging (a network funded by Fonds de Recherche du Québec – Santé) (P.G. and G.F.). C.M. holds a postdoctoral fellowship from CIHR.

Financiadores	Número del financiador
Fonds de Recherche du Québec-Santé
Hôpital du Sacré-Coeur de Montréal
National Institutes of Health (NIH)
Réseau québécois de recherche sur le vieillissement
Canadian Institutes of Health Research
National Institute on Aging	P30AG028383, R01AG027297, P50AG047270, K01AG024190
Center’s ADC	P30AG028383
CNRS Centre National de la Recherche Scientifique	ANR-10-MALZ-002
National Institute of Mental Health	R01MH091037, R01MH052711

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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10.1016/j.cub.2018.02.047

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Castonguay, D., Dufort-Gervais, J., Ménard, C., Chatterjee, M., Quirion, R., Bontempi, B., Schneider, J. S., Arnsten, A. F. T., Nairn, A. C., Norris, C. M., Ferland, G., Bézard, E., Gaudreau, P., Lombroso, P. J., & Brouillette, J. (2018). The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. Current Biology, 28(7), 1079-1089.e4. https://doi.org/10.1016/j.cub.2018.02.047

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title = "The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline",

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. The molecular changes leading to memory deficits during aging remain to be fully identified. Castonguay et al. provide genetic, behavioral, and molecular evidence that accumulation of the phosphatase STEP is a common molecular event that oppose synaptic strengthening and contributes to age-related memory deficits in mice, rats, monkeys, and humans.",

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author = "David Castonguay and Julien Dufort-Gervais and Caroline M{\'e}nard and Manavi Chatterjee and R{\'e}mi Quirion and Bruno Bontempi and Schneider, \{Jay S.\} and Arnsten, \{Amy F.T.\} and Nairn, \{Angus C.\} and Norris, \{Christopher M.\} and Guylaine Ferland and Erwan B{\'e}zard and Pierrette Gaudreau and Lombroso, \{Paul J.\} and Jonathan Brouillette",

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Castonguay, D, Dufort-Gervais, J, Ménard, C, Chatterjee, M, Quirion, R, Bontempi, B, Schneider, JS, Arnsten, AFT, Nairn, AC, Norris, CM, Ferland, G, Bézard, E, Gaudreau, P, Lombroso, PJ & Brouillette, J 2018, 'The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline', Current Biology, vol. 28, n.º 7, pp. 1079-1089.e4. https://doi.org/10.1016/j.cub.2018.02.047

TY - JOUR

T1 - The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline

AU - Castonguay, David

AU - Dufort-Gervais, Julien

AU - Ménard, Caroline

AU - Chatterjee, Manavi

AU - Quirion, Rémi

AU - Bontempi, Bruno

AU - Schneider, Jay S.

AU - Arnsten, Amy F.T.

AU - Nairn, Angus C.

AU - Norris, Christopher M.

AU - Ferland, Guylaine

AU - Bézard, Erwan

AU - Gaudreau, Pierrette

AU - Lombroso, Paul J.

AU - Brouillette, Jonathan

PY - 2018/4/2

Y1 - 2018/4/2

N2 - 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. The molecular changes leading to memory deficits during aging remain to be fully identified. Castonguay et al. provide genetic, behavioral, and molecular evidence that accumulation of the phosphatase STEP is a common molecular event that oppose synaptic strengthening and contributes to age-related memory deficits in mice, rats, monkeys, and humans.

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. The molecular changes leading to memory deficits during aging remain to be fully identified. Castonguay et al. provide genetic, behavioral, and molecular evidence that accumulation of the phosphatase STEP is a common molecular event that oppose synaptic strengthening and contributes to age-related memory deficits in mice, rats, monkeys, and humans.

KW - aging

KW - animal behaviors

KW - animal models

KW - hippocampus

KW - memory

KW - phosphatase STEP

UR - https://www.scopus.com/pages/publications/85044274134

UR - https://www.scopus.com/pages/publications/85044274134#tab=citedBy

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DO - 10.1016/j.cub.2018.02.047

M3 - Article

C2 - 29576474

AN - SCOPUS:85044274134

SN - 0960-9822

VL - 28

SP - 1079-1089.e4

JO - Current Biology

JF - Current Biology

IS - 7

ER -

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

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ASJC Scopus subject areas

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