The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.
Felipe C Ribeiro, Danielle Cozachenco, Elentina K Argyrousi, Agnieszka Staniszewski, Shane Wiebe, Joao D Calixtro, Rubens Soares-Neto, Aycheh Al-Chami, Fatema El Sayegh, Sara Bermudez, Emily Arsenault, Marcelo Cossenza, Jean-Claude Lacaille, Karim Nader, Hongyu Sun, Fernanda G De Felice, Mychael V Lourenco, Ottavio Arancio, Argel Aguilar-Valles, Nahum Sonenberg, Sergio T Ferreira
Alzheimer's & dementia : the journal of the Alzheimer's Association August 1, 2024 DOI: 10.1002/alz.14034 via PubMed
Summary
AI-generated from the abstractThe ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) activates signaling pathways (ERK1/2, mTOR, S6K1) in the hippocampus, rescuing long-term potentiation and memory deficits in two mouse models of Alzheimer's disease: mice infused with amyloid-β oligomers and aged APP/PS1 mice. The rescue depends on ERK signaling. HNK also corrects aberrant transcription in APP/PS1 mice. These results suggest HNK could be a therapeutic approach for Alzheimer's disease.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Alzheimer's disease mouse models (amyloid-β oligomer-infused mice and aged APP/PS1 mice) |
| Interventions | (2R 6R)-hydroxynorketamine (HNK) |
| Topics | Neuroplasticity |
| Keywords | Alzheimer's disease Hydroxynorketamine Mrna translation Neuroscience |
| Key finding | HNK rescues hippocampal synaptic plasticity and memory deficits in Alzheimer's disease mouse models via ERK-dependent signaling. |
Abstract
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. We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. 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-β oligomers (AβO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. 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. The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.