Alzheimer's & dementia : the journal of the Alzheimer's AssociationDec 23, 2025

The ketamine breakdown product (2R,6R)-hydroxynorketamine restores gene activity linked to immune response and protein production in a mouse model of Alzheimer's disease

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

HNK may normalize inflammation, RNA-translation, and synaptic-related transcriptional programs in aged APP/PS1 mouse hippocampus.

Evidence

This preclinical mouse transcriptomics experiment treated aged APP/PS1 mice with HNK 0.5 mg/kg daily for 14 days and analyzed hippocampal RNA-seq with GO and reactome pathways.

Caveat

The abstract reports pathway rescue rather than behavioral, protein-synthesis, or amyloid outcomes, so functional benefit in AD remains unshown.

Simplified

BACKGROUND: Hippocampal mRNA translation (i.e., protein synthesis) is crucial for synaptic plasticity and memory consolidation, and becomes defective in AD. We investigated here whether the ketamine metabolite HNK could rescue transcription profiles related to mRNA translation in aged APP/PS1 mice.

METHOD: Mice were treated with HNK (0.5 mg/kg, i.p.) or saline daily for 14 days, and hippocampal transcriptomic changes were assessed by RNA-seq. These data were then analyzed by gene ontology (GO) enrichment and reactome analysis.

RESULT: GO analyses revealed significantly upregulated pathways in APP/PS1 mice (compared to WT mice) that were corrected by HNK treatment. These included regulation of programmed cell death and response to hormones and stress. Reactome pathway analyses further implicated the innate immune system and, notably, three pathways associated with RNA metabolism and translation that were aberrantly regulated in APP/PS1 mice and were rescued by HNK.

CONCLUSION: Altogether, these results indicate that HNK rescues transcriptional programs associated with inflammation, impaired proteostasis, calcium signaling, and synaptic proteins in aged APP/S1 mice.