AAIC Conference (2025)
Kiyoung Kim, Doyeong Hwang, Soorin Yim, Kyungwook Lee, Dongyun Kim, Sungjoon Park, Daniel Gatti(Jackson Laboratory), Elissa Chesler(Jackson Laboratory), Amy Dunn(Jackson Laboratory), Kristen O'Conell(Jackson Laboratory)
Abstract
Background
Alzheimer’s disease (AD) is frequently associated with behavioral changes, including hyperactivity. In mouse models, hyperactivity is typically observed as an increase in walking distance; however, the underlying genetic and environmental factors remain poorly understood. In this study, we utilized the AD-BXD mouse model, a genetically diverse panel carrying familial AD mutations, as an excellent tool for investigating the complex etiology of AD. Understanding the genetic mechanisms contributing to hyperactivity in AD could provide valuable insights into disease progression and potential therapeutic targets.
Method
Hyperactivity was phenotyped in AD-BXD mice using the 5xFAD model, a well-established transgenic AD model. Behavioral data were collected via Y-maze distance measurements at two age points (6 months and 14 months) to assess activity changes with aging. Additionally, the impact of diet on hyperactivity was evaluated, with mice fed ad libitum either a normal control diet (“chow”; LabDiet 5K0G, 16% fat, 61% carbohydrates, 22% protein by kcal) or a high-fat/high-sugar (HFHS) diet (Research Diets D12451, 45% fat, 35% carbohydrate, 20% protein by kcal).
Result
At 14 months of age, 5XFAD mice showed a significant increase in walking distance compared to their 6-month-old counterparts, indicating a progressive hyperactivity phenotype with aging. In contrast, Ntg mice exhibited a decrease in walking distance over the same period, suggesting an age-related decline in activity. Female mice displayed a significant difference in delta distance (14 months - 6 months) between 5XFAD and Ntg mice, while no significant difference was observed in males. Diet had a significant effect on activity, with both 5XFAD and Ntg mice on the HFHS diet exhibiting increased walking distances at 6 months. The hyperactivity score was calculated as follows:
Hyperactivity score = (Δ distance14mo,5xFAD - Δ distance6mo,5xFAD) - (Δ distance14mo,Ntg - Δ distance6mo,Ntg)
Quantitative trait locus (QTL) mapping revealed a peak on chromosome 9 with a LOD score of 2.5 or higher in the Chow diet group. This region contains several AD-related genes, including Ntm, Kirrel3, Aplp2, St3Gal, and Tirap (MAL), suggesting their involvement in hyperactivity. Additionally, under the HFHS diet condition, a significant peak on chromosome 7 (LOD > 2.5) was observed, containing the Gas2 gene, which is implicated in lipid metabolism.
Conclusion
This study provides the first evidence that hyperactivity in AD-BXD mice is influenced by both genetic and environmental factors. The identification of QTLs on chromosomes 9 and 7, containing genes relevant to AD and lipid metabolism, offers new insights into the genetic mechanisms underlying hyperactivity in AD. Our findings also suggest that sex differences may play a role in the manifestation of hyperactivity, with female mice showing more pronounced changes than males. These insights may contribute to the development of new therapeutic strategies for managing hyperactivity and other behavioral symptoms in AD.