Adolescent intermittent ethanol exacerbates amyloid-β with age in the dorsal hippocampus of female TgF344-AD rats

Background Alcohol misuse increases Alzheimer's disease (ΑD) risk; however, the mechanisms linking these conditions are unknown. In rodents, chronic and acute ethanol increases amyloid-β (Aβ); however, most of those studies have been limited to a single sex or brain region. Objective This study explored how adolescent intermittent ethanol (AIE), alters Aβ in multiple regions of the brain in female and male TgF344-AD rats as they age. Methods From postnatal days 28–58, female and male TgF344-AD rats were administered either water (CON) or 5.0 g/kg ethanol (AIE; 20% ethanol w/v) via intragastric gavage on a 2-day on/off cycle. In Experiment 1, Aβ was measured in the medial prefrontal cortex, orbitofrontal cortex (OFC), piriform cortex (PC), entorhinal cortex (EC), ventral hippocampus (vHPC), and dorsal hippocampus (dHPC) in 6- and 10-month-old rats. In Experiment 2, in vivo microdialysis was used in 3-month-old female rats to measure how ethanol directly modulates Aβ levels in the dHPC. Results In the OFC, PC, EC, vHPC, and dHPC, Aβ 40 and Aβ 42 was higher in 6-month-old female TgF344-AD rats compared to males. However, at 10 months Aβ 40 and Aβ 42 levels were only elevated in the dHPC of AIE-treated females, compared to all other groups. An acute ethanol challenge at 3 months selectively evoked a sustained increase in interstitial fluid Aβ 40 levels in AIE-treated females. Conclusions In aged females, the dHPC is a region sensitive to ethanol-associated Aβ pathology. This may be due to disruptions in Aβ clearance in early life, which may have an additive effect on Aβ aggregation over the lifespan.