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

Abstract

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, Aβ₄₀ and Aβ₄₂ was higher in 6-month-old female TgF344-AD rats compared to males. However, at 10 months Aβ₄₀ and Aβ₄₂ 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 Aβ₄₀ 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.