As the most common form of dementia, Alzheimer?s disease (AD) is a neurodegenerative disorder that affects approximately 30 million people worldwide. AD is characterized by the aggregation of extracellular amyloid ? (A?) into amyloid plaques and intracellular tau into neurofibrillary tangles (NFTs), both of which begin to accumulate ~15 years before cognitive decline. Alcohol is among the most widely abused drugs in the world and problems arising from alcohol use disorder (AUD) represent a major public health concern. Epidemiological studies consistently identify AUD as a significant and independent predictor of AD in older adults. Heavy drinking in AD patients is associated with faster cognitive decline, suggesting that alcohol consumption may contribute to AD progression. However, it is unknown how alcohol intake during the pre- symptomatic period drives the AD pathogenesis, specifically, the production, clearance, and aggregation of A? and tau, the two pathological hallmarks of AD. In humans, monkeys, and rodents, the hippocampus is a brain area critical for memory formation and encoding and is especially vulnerable to the neurodegenerative processes and cognitive impairments associated with AD. The hippocampus is also compromised in AUD, with multiple lines of evidence suggesting that maladaptive changes in hippocampus-containing brain circuits leads to increases in fear- and anxiety-like behaviors and decreases in cognitive performance. Despite the availability of rodent models for alcohol dependence and mouse models for AD, very few studies have investigated the effects of alcohol exposure in AD mouse models. The central hypothesis of this proposal is that aberrant hippocampal excitatory synaptic function arising from ethanol exposure promotes the onset and progression of neuropathology and impairments in behavior and synaptic plasticity associated with AD. Toward this end, the work described in this proposal capitalizes on the research strengths of investigators in the Wake Forest Translational Alcohol Research Center and the Wake Forest Alzheimer?s Disease Research Center. We will combine a well-established model of ethanol dependence and a widely used AD mouse model to elucidate the interaction between AUD and AD at the molecular, behavioral, and synaptic levels. In addition, we will take advantage of an established cohort of monkeys undergoing a longitudinal study of ethanol consumption to determine if AD biomarkers correlate with ethanol intake. Collectively, these experiments will provide critically needed insight into the relationship of AUD and AD at the molecular, cellular, circuit, and whole-brain levels across animal models (rodents and non-human primates) and human subjects.
Epidemiological studies consistently identify a history of alcohol use disorder (AUD) as a significant and independent predictor of Alzheimer?s disease (AD) in older adults. However, it is unknown how alcohol intake during the pre-symptomatic period drives the AD pathogenesis, specifically, the production, clearance, and aggregation of A? and tau, the two pathological hallmarks of AD. The proposed studies will use a rodent model of alcohol dependence in an AD mouse model, as well as monkey with a history of alcohol consumption, to investigate the influence of alcohol exposure on the vulnerability to and progression of AD at the molecular, synaptic, and brain circuit levels across animal models.
