Investigating Whether Early Stage Memory Impairment Can be Detected in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by memory decline and dementia, and conclusively diagnosed postmortem from tangles and plaques. Plaques come from β-amyloid protein (Aβ), which damages the brain, especially the hippocampus, a structure vital for memory formation. However, whether plaques and tangles cause or result from AD is unclear. Our goal was to use a preclinical AD model to identify the early stages of cognitive dysfunction before AD becomes severe to enhance targeted interventions. We used a transgenic mouse (APP/PS1) that slowly develops plaques, with minimal expression around 5-6 months (young adult) with more expression by 12 months (middle-age). Our aim was to determine whether young adult mice would show cognitive symptomatology that could be used as a future metric for targeted treatment before AD advances further. We had three independent variables: Sex (Male, Female), Age (5-6, 8-10 months) and Genotype (APP/PS1, wildtype, WT). We used behavioral assays to assess spatial memory (hippocampal function), working memory (prefrontal cortex function), and anxiety (amygdala function). For my honor’s thesis, I focused on using the Morris Water Maze (MWM) to assess hippocampal function and the Open Field (OF) to assess anxiety and locomotion. In MWM, all groups were given four trials/day for four days with a probe trial to assess strategy immediately after the last trial on day 4. All groups swam shorter distances across days to show they were learning and revealed sex differences. The APP/PS1 males (young and old) learned the task more slowly than their WT male counterparts, but were using spatial strategies as demonstrated by the probe trial. For the females, all groups learned the task similarly, but the probe trial revealed that the APP/PS1 females (young and old) were using non-spatial strategies. Moreover, the males significantly swam shorter distances than the females, learning faster. The use of the visible platform task confirmed that the mice were capable of performing the swim task. For the OF, mice were placed in a square arena and given 10 minutes to explore and found sex differences in anxiety profile. All the female mice expressed similar anxiety profiles, whereas the APP/PS1 males had higher anxiety profiles than their WT males counterparts. These results revealed that there were sex-specific differences in cognition and anxiety profiles in the APP/PS1 mouse model. This indicates that individual characteristics are important to consider when using tailored interventions. In summary, these findings emphasize the potential for early detection and targeted treatment strategies to help mitigate AD progression.