Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Ketamine, an NMDA receptor antagonist, is used for anesthesia and has antidepressant properties.
• Major depressive disorder (MDD) is linked to Alzheimer's disease (AD), sharing hallmarks like neuroinflammation and synaptic dysfunction.
• The impact of ketamine on AD pathology remains largely unexplored.

Purpose of the Study:

• To investigate ketamine's effects on AD pathological markers in mouse models.
• To evaluate memory, amyloid pathology, and glial changes following ketamine administration.
• To analyze transcriptomic alterations induced by ketamine in the context of AD.

Main Methods:

• Administered single-dose ketamine to amyloid-β oligomer (AβO) injected mice.
• Chronically treated transgenic APP/PS1 mice with ketamine for 35 days.
• Performed memory tests, immunohistology, and RNA sequencing on mouse hippocampi.

Main Results:

• Ketamine protected against AβO-induced memory impairment, but chronic treatment showed no memory benefit in APP/PS1 mice.
• Chronic ketamine induced an AD-like transcriptional profile in wildtype (WT) mice.
• Ketamine modulated gene expression related to synaptic transmission, protein translation, and glial function, with opposing effects in WT and APP/PS1 mice.

Conclusions:

• Chronic low-dose ketamine elicits a distinct transcriptional and cellular response in AD models.
• Ketamine induces an AD-like transcriptional signature in WT mice, suggesting potential modulation of AD risk.
• Clinical use of low-dose ketamine in individuals at risk for or diagnosed with AD warrants careful consideration.