Impact of Prenatal alcohol on Alzheimer's disease related pathology and cognitive impairment

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Project Summary: Persons with fetal alcohol spectrum disorders (FASD) experience life-long neurocognitive deficits as well as social and adaptive dysfunction, but we know virtually nothing about their health as they age. We recently reported that prenatal alcohol-exposure (PAE) resulted in long-term alteration in cranially-directed blood flow and reduced recovery of function after an acute ischemic injury in adulthood. This suggests that PAE is an important risk factor for cerebrovascular diseases and consequently, for dementia and Alzheimer's disease (AD). Young PAE rats also exhibit cognitive deficits and importantly, increased depression-related behaviors which are early predictors of AD. Therefore, in these studies, we will utilize the transgenic TgF344-AD rat which develops AD pathology in aging, to test the hypothesis that PAE will accelerate cerebro-vascular impairment, behavioral dysfunction and the accumulation of AD-related brain lesions, leading to premature aging. Moreover, we will specifically test whether male and female PAE offspring differ in their accumulation of AD-related anatomical and neurobehavioral pathology. We will implement a vapor-chamber model of repeated PAE, to achieve consistent binge-like maternal exposure episodes, spanning the fetal neurogenic period. PAE and control offspring will be assessed from young adults to 15 months of age, by ultrasound imaging of cranially directed blood flow, by a panel of behavioral assays for cognitive dysfunction and depression-like phenotypes, as well as a panel of histological assays for AD pathology. The investigators have a history of collaboration and application of experimental rigor in their areas of complementary expertise in models of aging and PAE, which supports the feasibility of the proposed studies. These studies are significant because they address a critical knowledge gap about the link between early life adversity, i.e., PAE, and the onset of AD. We expect that, if these studies do link PAE to accelerated AD pathology, they will help redefine FASD as a disorder of premature aging and strengthen the premise for investigating mechanisms that link PAE to aging, as well as interventions that decouple this linkage.