Targeting the Post-Synaptic Proteome in Alzheimer Disease with Psychosis

Abstract

INTRODUCTION: Individuals with Alzheimer Disease who develop psychotic symptoms (AD+P) experience more rapid cognitive and functional decline, and have reduced indices of synaptic integrity, relative to those without psychosis (AD-P). We hypothesized that the postsynaptic density (PSD) proteome is altered in AD+P relative to AD-P, and that this proteomic signature could be used to nominate novel pharmacotherapies. METHODS: Liquid-Chromatography/Mass Spectrometry analysis of PSDs from dorsolateral prefrontal cortex of AD+P, AD-P, and cognitively normal elderly subjects. RESULTS: The PSD proteome signature of AD+P was characterized by lower levels of a network of kinases, proteins regulating Rho GTPases, and other regulators of the actin cytoskeleton. Potential novel therapies identified included the C-C Motif Chemokine Receptor 5 inhibitor, maraviroc. DISCUSSION: AD+P is characterized by broad changes in the PSD proteome. Further testing of potential therapies for their ability to reverse these changes and reduce psychotic-like behaviors in model systems is warranted.