Role of Dopamine in Alcohol-Enhanced Alzheimer’s Disease Progression

Wake Forest University Health Sciences, Winston-Salem NC

Investigators

Abstract

PROJECT SUMMARY Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive deficits. Although reductions in dopamine within cognitive and reward circuits have been seen in post-mortem AD brains, changes in dopamine transmission remain under-researched, particularly in combination with chronic ethanol (EtOH) exposure. Neuropsychiatric symptoms (NPS), such as depression and apathy, are increasingly recognized as early signs of AD and have been linked to the disease's onset and progression. The presence of NPS is associated with a higher risk of transitioning from mild cognitive impairment to AD. Interestingly, NPS are also common in alcohol use disorder (AUD). Dopamine, a crucial regulator of motivation and decision-making, also plays a significant role in learning and memory processes. Deficits in dopamine transmission are strongly linked to apathy and are thought to contribute to other NPS. Dopamine deficits are a known consequence of AUD, and are also thought to occur in AD. Dopamine dysfunction may connect the neuropsychiatric and cognitive symptoms observed in both AD and AUD. The adverse effects of AUD on AD progression are well-established. Preclinical research, including studies from our lab, has shown that chronic EtOH exposure reduces dopamine release and increases its uptake, resulting in hypodopaminergia. This study will examine how dopamine transmission changes throughout progression of AD-associated pathology and the effect of EtOH exposure. Human AD studies have identified decreased dopamine in various neuronal circuits, and correcting these deficits is gaining interest as a method to slow AD symptom progression. Targeting proteins involved in dopamine release and reuptake is one approach, with Synaptogyrin-3 (Syngr-3) being a novel promising candidate. Syngr-3 is a synaptic vesicle protein highly expressed in limbic brain regions. In a mouse model of AD, Syngr-3 levels in the nucleus accumbens (NAc) were found to be reduced. Similarly, there was a negative correlation between EtOH intake and Syngr-3 expression, suggesting that reductions in Syngr- 3 could be a common underlying mechanism of hypodopaminergia in both EtOH and AD. The central hypothesis of this project is that hypodopaminergia contributes to the rapid progression of AD symptoms, and this is exacerbated by EtOH exposure. Genetic manipulation of Syngr-3 levels will be used to document its contribution to hypodopaminergia and AD symptoms.