Alzheimer's' disease (AD) affects more than 5 million people in the United states and is a significant contributor to dementia worldwide and to date, there is no cure. Because alcohol abuse is strongly associated with AD and AD-related dementias (ADRD), we aim to expand the funded research award (R00AA025386) to understand if alcohol-related liver disease is a contributing factor to neuroinflammation, neurodegeneration and cognition impairment, thus contributing to early-onset AD progression. Moreover, as older individuals are more sensitive to the detrimental effects of alcohol, we will investigate the role of liver-derived complement activation as a component of ?inflammaging? and ADRD. Importantly, we will use novel methods to assess the metabolic consequences of chronic inflammation in the liver and brain by measuring bioactive lipid mediators, known as oxylipins. Because neuroinflammation is a fundamental process contributing to neurodegeneration, and persistent activation of complement contributes to chronic inflammation, It is our working hypothesis that liver-derived complement activation, occurring after ethanol exposure, can perpetuate chronic inflammation and tissue injury in the brain, leading to impairments in cognition during early-onset ADRD. Findings from this supplement will be the first to describe complement as a key communicatory factor participating in liver-brain crosstalk in AD caused by alcohol exposure. We will also be able to directly investigate if alcohol-related liver disease is a causative factor for AD development. Importantly, findings from these studies may provide new therapeutic targets to prevent the onset and progression of AD and ADRD. This proposal, with explicit goals to better understand the biology of AD and ADRD, capitalizes on my previously funded research, my expertise in cytokine biology, lipid oxidation and mechanistic toxicology, and the established core facilities present at the University of Colorado. The experiments we propose are therefore well within the scope of NOT-AG-18-008.
Alzheimer's disease (AD) is the most common form of progressive dementia in the aged. Alcohol abuse may potentiate the pathogenesis of AD by eliciting profound systemic and local activation of complement, resulting in neuroinflammation and neuronal damage. Pharmacologic intervention of complement may be a promising approach to attenuate the pathogenesis of AD to accelerate the production of specialized pro-resolving lipid mediators to normalize inflammation in peripheral tissues, including the brain.
| Kim, Adam; McCullough, Rebecca L; Poulsen, Kyle L et al. (2018) Hepatic Immune System: Adaptations to Alcohol. Handb Exp Pharmacol : |
| McCullough, Rebecca L; McMullen, Megan R; Poulsen, Kyle L et al. (2018) Anaphylatoxin Receptors C3aR and C5aR1 Are Important Factors That Influence the Impact of Ethanol on the Adipose Secretome. Front Immunol 9:2133 |
| McCullough, Rebecca L; McMullen, Megan R; Sheehan, Megan M et al. (2018) Complement Factor D protects mice from ethanol-induced inflammation and liver injury. Am J Physiol Gastrointest Liver Physiol 315:G66-G79 |
