Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the sixth leading cause of death in the US. AD is more prevalent in females than males. While estrogen provides neuroprotection in females, sex mediated differences in the development of AD pathology are not fully elucidated. Therefore, a comparison of the events that develop between sexes in the early-stage of AD pathology may reveal new potential targets for more effective therapeutic intervention. To address sex differences, we analyzed early stage 9-month male and female TgF344-AD (Tg-AD) rats, an AD model carrying the APPswe and Presenilin 1 (PS1ΔE9) mutations that develops progressive age-dependent AD pathology similar to humans. Using active place avoidance (aPAT) tests that assess hippocampal-dependent spatial learning and memory, we found significant deficits in Tg-AD females compared to wild type females, but no significant difference between the two male genotypes. Moreover, significant sex differences were observed in that Tg-AD females outperformed Tg-AD males in several measures of the aPAT test. Unexpectedly, Tg-AD females displayed higher levels of hippocampal amyloid plaques and amoeboid microglia than their Tg-AD male littermates. Furthermore, Tg-AD females experienced less hippocampal neuronal loss and had higher GluA2 subunit levels than Tg-AD males. Based on our findings, we propose that estrogen may protect females against cognitive impairment at early stages of AD by regulating GluA2 levels independently of amyloid plaque deposition and gliosis. Elucidating this potential protective mechanism of action of estrogen in AD could lead to new targets for early intervention.

Low-Dose Radiation Therapy Impacts Microglial Inflammatory Response without Modulating Amyloid Load in Female TgF344-AD Rats

“…This difference may be due to a more advanced pathology in females than in males, leading to pathological process too deeply rooted to be reversed or significantly halted. Indeed, the sex effect in AD, with an enhanced pathology hallmarks in females, is commonly described in other AD mouse models [33][34][35] and some studies suggest also this difference in TgAD rats [23,36,37]. Further studies are consequently needed to validate this difference in our model on the different amyloid peptides studied.…”