Fingolimod mitigates synaptic deficits and psychosis-like behavior in APP/PSEN1 mice

Area of Science:

• Neuroscience
• Pharmacology
• Alzheimer's Disease Research

Background:

• Psychosis is a severe symptom of Alzheimer's disease (AD), leading to faster cognitive decline.
• Current treatments for AD-associated psychosis are insufficient, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the efficacy of fingolimod, an FDA-approved multiple sclerosis drug, as a potential treatment for psychosis in Alzheimer's disease.
• To assess fingolimod's effects on synaptic protein expression and psychosis-related behaviors in a preclinical AD model.

Main Methods:

• Utilized APPswe/PSEN1dE9 transgenic mice and wild-type littermates, treated with fingolimod or saline.
• Quantified psychosis-associated behaviors using open field, pre-pulse inhibition, and acoustic startle habituation tests.
• Analyzed synaptic protein abundance in cortical homogenates and postsynaptic densities via liquid chromatography/mass spectrometry.

Main Results:

• Fingolimod treatment significantly increased synaptic protein levels in cortical homogenates.
• Fingolimod administration normalized psychosis-associated behaviors in APPswe/PSEN1dE9 mice compared to saline controls.
• Fingolimod preferentially altered mitochondrial-related proteins, which correlated with behavioral improvements.

Conclusions:

• Fingolimod demonstrates preclinical efficacy in ameliorating psychosis-associated behaviors and restoring synaptic protein levels in an AD mouse model.
• These findings support further investigation of fingolimod as a therapeutic candidate for psychosis in Alzheimer's disease.
• Replication studies using diverse AD models and comprehensive behavioral and proteomic assessments are recommended.