In contrast, evidence that alcohol can increase amyloid levels comes from several studies. In vitro, low ethanol exposure, equivalent to moderate alcohol usage, decreased Aβ binding to neurons and thereby reduced neurotoxic actions of Aβ [86] which may account for protective actions at low to moderate doses. Exacerbation of AD pathogenesis by alcohol has been reported using both in vitro and in vivo studies. In human, SK-N-MC neuroblastoma cells ethanol upregulated BACE1 expression and Aβ production, as well as increased reactive oxygen species (ROS) production, cyclooxygenase-2 (COX-2) expression and PGE2 production [32]. Ethanol exposure of mice for 4 weeks increased APP levels and BACE1 expression, promoted Aβ production, increased plaque deposition, and worsened cognitive deficits [33]. Adult rats fed alcohol for 5 weeks had increased levels of APP and BACE1 in several brain regions and increased presenilin-1 and nicastrin in the hippocampus [34]. Long-term alcohol consumption significantly impaired spatial memory in adult rats, which may be a contributing factor to development of AD [87]. These findings show that alcohol increases amyloidogenic processing, a mechanism which could contribute to plaque burden.
