Evaluation of the synergistic effects of developmental and adult alcohol exposure on Alzheimer's-related phenotypes

University Of Tennessee Health Sci Ctr, Memphis TN

Investigators

Abstract

Ethanol exposure has been proposed as an environmental risk factor for developing Alzheimer’s disease (AD) or other forms of dementia. Initial evidence has demonstrated this relationship by showing that high levels of ethanol exposure in adults is linked to higher dementia risk in human and animal studies. Recently, evidence has begun to suggest that developmental ethanol exposure may also be a risk factor although the data is not conclusive at this point. Previous work has used mouse models and prenatal ethanol exposure. However, one of the brain regions most affected in Alzheimer’s disease is the hippocampus and its related structure, the entorhinal cortex. The hippocampus is highly susceptible to ethanol-induced alterations during the brain growth spurt which occurs during the third trimester in humans and during the first 10 days of postnatal life in rodents. The link between this time of ethanol exposure and possible AD phenotypes has not been explored. Further, because individuals with prenatal ethanol exposure are at higher risk for alcohol abuse disorders as adults, there is a higher likelihood for ethanol exposures at multiple times throughout the lifespan. Therefore, a 2-hit model is proposed where early exposure disrupts hippocampal development in a way that sensitizes the neurons to adult ethanol exposure to ultimately enhance the potential for later damage. These experiments will test the following hypotheses: 1) Ethanol exposure during the time when the hippocampal formation is most affected by developmental ethanol exposure will enhance the risk for developing AD-like phenotypes. 2) Developmental ethanol exposure will act synergistically with adult ethanol exposure to enhance the risk for AD-like phenotypes. 3) Both of these effects will be impacted by sex. In these experiments the 5xFAD transgenic mice, which contain several alleles that have been linked to AD, will be evaluated. Mice will be given ethanol exposure either during development only, during adulthood only or at both times. Ethanol exposed mice will be compared to saline and unexposed controls, and both transgenic and wild-type mice will be evaluated. Aim 1 will evaluate whether these mice show early expression of AD-related behaviors in a number of behaviors tested (e.g. Morris water maze). Aim 2 will evaluate whether there are differences in the levels or patterns of expression of the amyloid beta peptide as a marker for abnormal pathology in the same mice used in Aim 1. If this hypothesis is correct, a new avenue of experiments of research will be opened up including: 1) examination of the impact of varying dose and timing of ethanol exposure, 2) evaluation of differing genetic background and 3) examination of the molecular pathways that contribute to any synergistic actions. Further, as the first individuals diagnosed with fetal alcohol spectrum disorders (FASD) are now approaching middle age, this data would be crucial in counseling individuals with FASD as to their risk for developing AD, particularly in those individuals who had alcohol abuse disorders. Moreover, the results of these studies have the potential to open up a host of additional studies focusing on a potentially new risk factor for AD that would need further exploration.