Effects of binge alcohol administration on tauopathy and neuroinflammation in PS19 mice

Abstract

AbstractBackgroundIt is estimated that 50 million people worldwide are suffering from dementia, the most common being Alzheimer’s disease (AD). Even as the population ages and the incidence of AD increases, there are limited disease‐modifying treatments to date. Alcohol use disorders (AUD) have been identified as a modifiable risk factors for developing AD. Heavy alcohol intake in elderly individuals is associated with more rapid progression of AD pathology and an elevated neuroinflammatory state. The objective of this study was to investigate the interaction of high ethanol ‘binge’ treatments in a mouse model of tauopathy.MethodPS19 mice, a widely used tauopathy model, were subjected to a 5‐week binge paradigm of IP ethanol administration, 3.0g/kg, three times per week, beginning at 6 months of age. Prior to initiation of the binge ethanol regimen, mice received subcutaneous biotransponder implantations to record body temperature changes in response to ethanol. Blood ethanol concentrations were determined in a subset of mice at 30 minutes following the last ethanol administration. Frailty measures were completed one week after ethanol administration. NanoString unbiased gene expression, MesoScale Discovery ELISA, Western blotting, and Immunohistochemistry were performed to examine neuroimmune changes and markers of tau pathology.ResultOverall, ethanol treatment resulted in reduced body weight, which was further exacerbated in female PS19 mice.. Measures of frailty (i.e. cerebellar ataxia and grip strength) were impaired in PS19 mice, however, female PS19 mice receiving ethanol treatment had the greatest impairments compared to WT controls. Alterations in inflammatory signaling pathways were observed in the PS19 animals receiving alcohol treatment compared to PS19 or WT mice.ConclusionWe have examined the result of intermittent alcohol exposure on tau pathogenesis. In the present study we found that alcohol can induce biometric and behavioral changes in mice, which are further exacerbated by alcohol. Transcriptomic analysis indicated changes in both innate and inflammatory signaling, suggesting a increased inflammatory response in the ethanol treated animals. Taken together, these results suggest that intermittent environmental influences, such as ethanol, can result in more rapid progression of AD pathogenesis.