Alzheimer's & dementia : the journal of the Alzheimer's AssociationJun 27, 2024

(2R,6R)-hydroxynorketamine, a ketamine breakdown product, restores protein production, brain cell connections, and memory in mouse models of Alzheimer's disease

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Updated Jun 27, 2026

Abstract

Essence

The ketamine metabolite HNK rescued hippocampal signaling, synaptic plasticity, and memory deficits in Alzheimer's disease mouse models.

Evidence

A preclinical mouse-model experiment tested HNK in amyloid-beta oligomer-infused and aged APP/PS1 mice, measuring ERK/mTOR/S6 signaling, hippocampal , transcription, and memory.

Caveat

The abstract provides animal-model evidence only, so it does not establish safety or benefit in people with Alzheimer's disease.

Simplified

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, (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-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.

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.

HIGHLIGHTS: 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.

Key numbers

20%

Decrease in Protein Synthesis

Reduction in protein synthesis observed in hippocampal slices treated with .

0.5 mg/kg

Memory Deficits Reversed in

Dosing of administered to for memory recovery.

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(2R,6R)-hydroxynorketamine, a ketamine breakdown product, restores protein production, brain cell connections, and memory in mouse models of Alzheimer's disease

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