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

INTRODUCTION

Current treatments for psychosis in Alzheimer's disease (AD), a syndrome characterized by more rapid deterioration and reduced synaptic protein abundance relative to non-psychotic AD, are inadequate. Fingolimod, a currently US Food and Drug Administration (FDA)-approved pharmacotherapy for multiple sclerosis, alters synaptic protein expression and warrants preclinical appraisal as a candidate pharmacotherapy for psychosis in AD.

METHODS

Presenilin and amyloid precursor protein transgenic mice (APPswe/PSEN1dE9) and wild-type mice were randomized to fingolimod or saline for 7 days. Psychosis-associated behaviors were quantified by open field testing, pre-pulse inhibition of the acoustic startle response testing, and habituation of the acoustic startle response testing. Synaptic proteins were quantified by liquid chromatography/mass spectrometry in homogenate and postsynaptic density fractions.

RESULTS

Fingolimod treatment increased the synaptic protein abundance in cortical homogenates and normalized psychosis-associated behaviors in APPswe/PSEN1dE9 mice relative to saline. Mitochondrial-related proteins were preferentially altered by fingolimod treatment and correlated with improvements in psychosis-associated behaviors.

DISCUSSION

Preclinical studies employing complementary psychosis-associated behavioral assessments and proteomic evaluations across multiple AD-related models are warranted to replicate the current study and further investigate fingolimod as a candidate treatment for psychosis in AD.