Ketamine promotes the amyloidogenic pathway by regulating endosomal pH

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Ketamine, an anesthetic, can cause cognitive dysfunction and neuroinflammation.
• Amyloidogenic products like CTF-β and Aβ also induce neuroinflammation and cognitive impairment.
• The link between ketamine and the amyloidogenic pathway remains unclear.

Purpose of the Study:

• To investigate if ketamine regulates the amyloidogenic pathway.
• To determine ketamine's effect on endosomal pH and its relation to amyloid precursor protein (APP) processing.
• To explore the role of sodium hydrogen exchanger 6 (NHE6) in ketamine-induced amyloidogenesis.

Main Methods:

• Utilized C57BL/6J mouse and SH-SY5Y cell models with varying ketamine doses.
• Employed Western blotting, confocal imaging, and flow cytometry to analyze protein levels and endosomal pH.
• Investigated the effect of monensin (pH restoration) and NHE6 knockdown on ketamine's actions.

Main Results:

• Ketamine increased endosomal BACE1 and CTF-β, while decreasing NHE6 and APP levels.
• Ketamine treatment lowered endosomal pH in SH-SY5Y cells.
• Restoring endosomal pH with monensin or knocking down NHE6 counteracted ketamine's effects on the amyloidogenic pathway.

Conclusions:

• Ketamine promotes the amyloidogenic pathway by reducing NHE6 and consequently lowering endosomal pH.
• This mechanism contributes to ketamine-induced neuroinflammation and cognitive dysfunction.
• Targeting NHE6 or endosomal pH may offer therapeutic strategies for ketamine-related neurological effects.