Tuesday, April 23, 2024
4/23/2024
Project Summary / Abstract Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, accounting for approximately half to two-thirds of all cases of dementia. It is associated with cognitive impairments and an increase in ß-amyloid plaque (Aß) deposits. Moreover, alcohol use disorder (AUD) has been associated with neurodegeneration and cognitive impairments, but the role of alcohol dependence on AD has been somewhat controversial. Recent evidence suggests a likely role for alcohol use as a risk factor in onset and severity of Alzheimer's disease, however overall reports have been mixed. Given the pervasive use of alcohol, it is critical to understand the potential impact of alcohol drinking on AD. We will examine the impact of a history of alcohol dependence on the onset and severity of behavioral and neuropathological symptoms associated with AD. We will further examine how alcohol dependence influences neural network function in AD. We will assess whether or not treatment with Memantine can reverse the behavioral and neuropathological symptoms. We hypothesize that a history of alcohol dependence will result in an earlier onset of cognitive impairment in AD mice as well as a greater presence of Aß deposits and that these deficits will be rescued by chronic treatment with Memantine. We hypothesize that a history of alcohol dependence in AD mice will alter network connectivity (decrease modularity and change hub regions) and that these effects will be alleviated by Memantine treatment. Alterations of functional network connectivity that are caused by alcohol dependence will be assessed in a mouse model of AD. These changes will be compared with the brain-wide spread of Aß deposits, which will indicate the way in which AD affects brain-wide function, potentially beyond brain areas with signs of neuropathology. Furthermore, the role of alcohol dependence in AD (e.g., changes in network connectivity and behavioral and neuropathological symptoms) will be examined using a relevant translational preclinical model of AUD. Cognitive function, anxiety-like behavior, and irritability-like behavior will be assessed in AD and wildtype alcohol drinking and alcohol naive mice. The number and location of Aß deposits will be assessed AD mice. Differences in network connectivity in AD and wildtype mice will be examined using hierarchical clustering and graph theory. If alcohol dependence is found to impact the onset of neurological and behavioral symptoms of AD, then this will be a highly significant finding that will have a broad impact on preclinical and clinical research. These potential findings may also directly influence public guidelines for alcohol consumption, especially in those with a familial risk for AD.
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