Animal Models of Psychosis in Alzheimer Disease

Abstract

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.

Keywords: Alzheimer disease; Psychosis; animal model; dementia; mouse; preclinical.

Figure 1.. Behavioral paradigms for assessment of psychosis-associated behaviors in mice.

(A) Radial Arm Maze. The radial arm apparatus contains identical arms radiating from a central location, each of which may or may not be baited with a food reward. Reference and working memory can be assessed, respectively, through various measurements of the mouse’s ability to recall which arms contain the food reward and which arms the mouse had previously explored. (B) Open Field Test. The mouse is exposed to a novel enclosure containing an evenly illuminated open field and various measurements of locomotive activity can be recorded. (C) Social Recognition. The mouse being assayed is exposed to one novel mouse and one familiar mouse, each enclosed in separate enclosures within a three-chamber apparatus. Under typical conditions in wild-type mice, interactions initiated by the mouse undergoing assessment preferentially involve the novel, rather than familiar mouse. (D) Prepulse Inhibition of the Acoustic Startle Response. Using an accelerometer attached to the base of a mouse enclosure, the mouse’s startle responses are recorded for two types of trials: trials to analyze basal startle responsiveness (left panel) and trials with a prepulse to analyze the attenuation of the startle response (right panel). (E) Tube Test. Two cage mate mice are positioned opposing each other within a narrow tube and dominance is assayed by observing which mouse retreats from the tube apparatus.

Figure 2.. A hypothetical model for conceptualizing syndromic variants of Alzheimer Disease (AD).

Core AD-related neuropathologies at the molecular and cellular levels give rise to impairments at the systems level, in turn generating specific symptoms which define syndromes in AD. Genetic and environmental variability have been shown to modify how these pathologies manifest as symptoms, driving the emergence of distinct syndromes. Consideration of higher order systems in the evaluation of classical AD-related models facilitates the development of increasingly complex AD syndrome-related models, which may eventually give rise to syndrome-specific pharmacotherapies.