The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease

被引：1

作者：

Ribeiro, Felipe C. ^{[1
]}

Cozachenco, Danielle ^{[1
]}

Argyrousi, Elentina K. ^{[2
]}

Staniszewski, Agnieszka ^{[2
]}

Wiebe, Shane ^{[3
]}

Calixtro, Joao D. ^{[1
]}

Soares-Neto, Rubens ^{[1
]}

Al-Chami, Aycheh ^{[4
]}

El Sayegh, Fatema ^{[4
]}

Bermudez, Sara ^{[3
]}

Arsenault, Emily ^{[4
]}

Cossenza, Marcelo ^{[5
]}

Lacaille, Jean-Claude ^{[6
,7
]}

Nader, Karim ^{[8
]}

Sun, Hongyu ^{[4
]}

De Felice, Fernanda G. ^{[1
,9
,10
,11
]}

Lourenco, Mychael V. ^{[1
]}

Arancio, Ottavio ^{[2
]}

Aguilar-Valles, Argel ^{[4
]}

Sonenberg, Nahum ^{[3
]}

Ferreira, Sergio T. ^{[1
,11
,12
]}

机构：

[1] Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil

[2] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[3] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada

[4] Carleton Univ, Dept Neurosci, Ottawa, ON K1S 5B6, Canada

[5] Fluminense Fed Univ, Biomed Inst, Dept Physiol & Pharmacol, Niteroi, RJ, Brazil

[6] Univ Montreal, Ctr Interdisciplinary Res Brain & Learning, Dept Neurosci, Montreal, PQ, Canada

[7] Res Grp Neural Signaling & Circuits, Montreal, PQ, Canada

[8] McGill Univ, Dept Psychol, Montreal, PQ, Canada

[9] Queens Univ, Ctr Neurosci Studies, Dept Biomed & Mol Sci, Kingston, ON, Canada

[10] Queens Univ, Dept Psychiat, Kingston, ON, Canada

[11] D Or Inst Res & Educ, Rio De Janeiro, RJ, Brazil

[12] Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Rio De Janeiro, RJ, Brazil

来源：

ALZHEIMERS & DEMENTIA | 2024年 / 20卷 / 08期

关键词：

Alzheimer's disease; hydroxynorketamine; memory; mRNA translation; synaptic plasticity; DEPRESSIVE-LIKE BEHAVIOR; AMYLOID-BETA OLIGOMERS; MAMMALIAN TARGET; INHIBITION; DEFICITS; HYDROXYNORKETAMINE; PHOSPHORYLATION; DYSFUNCTION; ACTIVATION; IMPAIRMENT;

D O I：

10.1002/alz.14034

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-beta oligomers (A beta O)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD.

引用

页码：5398 / 5410

页数：13

共 43 条

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