Targeting the post-synaptic proteome has therapeutic potential for psychosis in Alzheimer Disease

Abstract Individuals with Alzheimer Disease who develop psychotic symptoms (AD + P) experience more rapid cognitive decline and have reduced indices of synaptic integrity relative to those without psychosis (AD-P). We sought to determine whether the postsynaptic density (PSD) proteome is altered in AD + P relative to AD-P, analyzing PSDs from dorsolateral prefrontal cortex of AD + P, AD-P, and a reference group of cognitively normal elderly subjects. The PSD proteome of AD + P showed a global shift towards lower levels of all proteins relative to AD-P, enriched for kinases, proteins regulating Rho GTPases, and other regulators of the actin cytoskeleton. We computationally identified potential novel therapies predicted to reverse the PSD protein signature of AD + P. Five days of administration of one of these drugs, the C-C Motif Chemokine Receptor 5 inhibitor, maraviroc, led to a net reversal of the PSD protein signature in adult mice, nominating it as a novel potential treatment for AD + P.