Animal Models of Psychosis in Alzheimer Disease

© 2019 American Association for Geriatric Psychiatry Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes

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