The offspring of mothers harboring APP/PS1 mutations presents early changes in memory and brain metabolism.

Abstract

Previous studies suggested that individuals with a maternal history of Alzheimer's Disease (AD) are at higher risk of developing AD than individuals with a paternal history of AD. One could suggest that intra-uterine interactions might be responsible for elevating this risk. In this context, AD rodent models are highly suited for improving our understanding of this matter since animals reach adulthood in a few months. Here, we aimed at investigating changes in memory-related processes and brain metabolism on the offspring born to transgenic mothers harboring human APP/PS1 mutations. We hypothesized that offspring born to AD-transgenic mothers will present early memory and brain glucose metabolism changes. Rats born to F344-AD (Tg-AD) mothers and wild-type fathers (WT), the maternal AD group, and rats born to WT mothers and Tg-AD fathers, the paternal AD group, were evaluated in two different time-points: ∼5.5, and ∼9.5 months. To assess spatial working memory, spontaneous alternation behavior was evaluated in the Y-maze test. Furthermore, micro-PET [18 F]FDG was used to assess brain glucose metabolism (SUVr normalization, pons as reference region). Y-maze test demonstrated that rats born to transgenic mothers presented memory disturbances, indexed by spontaneous alternation, at ∼5.5 months (p = 0.0028, Figure 1A) and ∼9.5 months (p = 0.0062, Figure 1B), while rats born to WT mothers and Tg-AD fathers exhibited a decline in spontaneous alternation only at ∼9.5 months (p = 0.0181, Figure 1B). No changes were found in brain glucose metabolism at ∼5.5 months for both groups. However, rats born to AD-Tg mothers present brain glucose hypermetabolism at ∼9,5 months. Our findings demonstrate that rats born to AD-Tg mothers harboring APP/PS1 mutations present cognitive decline and brain glucose metabolism abnormalities earlier than those born to WT mothers. Further studies are needed to understand the biological basis behind this phenomenon.