Modulation of BPSD phenotypes in Alzheimer's disease by cognitive stress, voluntary physical activity, and social isolation: Studies in 3xTg-AD mice and non-transgenic C57BL/6J counterparts

Abstract

Behavioral and Psychological Symptoms of Dementia (BPSD) are a significant challenge throughout the progression of Alzheimer's Disease (AD), imposing substantial strain on both patients and their families. These symptoms are often underexamined due to their complex and heterogeneous nature. In this context, animal models replicating these symptoms provide a valuable tool for isolating specific behaviors and studying their evolution across age and environmental conditions. This doctoral thesis investigates BPSD- like phenotypes using a triple-transgenic mouse model of AD (3xTg-AD) and non-transgenic C57BL/6J mice, across three experimental paradigms that model cognitive stress, voluntary physical activity, and social isolation. In the first study, mice underwent the Morris Water Maze (MWM) test at two distinct ages (12 and 16 months). Their performance, in what is considered a stressful environment for mice, was assessed by analyzing the swimming strategies employed to locate a submerged platform. Employing robust statistical methods to account for interindividual and baseline variations, circling behavior was identified as a unique BPSD-like pattern within the transgenic group. The second study allowed mice access to a running wheel, and their circadian activity patterns were recorded for one month. Results indicated sex-dependent differences in behavioral regulation, with transgenic males displaying patterns consistent with disruptions reported in human AD. In the third study, the impact of social isolation was evaluated in 13-month-old mice. A distinctive digging pattern, mimicking obsessive- compulsive behavior, was identified exclusively in isolated animals, representing a novel non-cognitive marker of BPSD-like disruption. Together, these findings highlight the subtle, context-dependent nature of BPSD-like behaviors and underscore the importance of environmental and individual factors in shaping their expression. This work contributes to the refinement of translational models for AD and enhances the understanding of BPSD under experimentally controlled conditions.

Date of Award	29 Oct 2025
Original language	English
Awarding Institution	Universitat Autònoma de Barcelona (UAB)
Supervisor	Lidia Gimenez Llort (Director)