Alcohol is the most commonly abused substance and Alzheimer?s disease (AD) is the most common neurodegenerative disease. Alcohol abuse is a significant risk factor for the development of AD and this intersection of alcohol abuse and AD presents an enormous public health concern. Chronic, heavy alcohol use is associated with a higher risk of developing AD and accelerated progression of the disease. The clinical phase of AD is preceded by a decades long preclinical phase that is characterized by early deposition of amyloid b (Ab) and neuronal loss in the locus coeruleus (LC), a norepinephrine nucleus in the brainstem. We propose a novel mechanism by which chronic alcohol consumption renders LC neurons vulnerable to degeneration. We recently discovered a novel cellular mechanism that selectively induces mitochondrial oxidant stress in axons. Cytosolic monoamines, including norepinephrine, are metabolized by monoamine oxidase (MAO) enzymes and the electrons generated from this process are directly shuttled into the mitochondrial intermembrane space. This produces increased mitochondrial oxidant stress selectively in axons. We propose that chronic alcohol consumption activates this novel mechanism of axonal mitochondrial oxidant stress leading to a degenerative cascade in LC neurons. Our pilot studies suggest that chronic, intermittent alcohol consumption decreased VMAT2 mRNA and increased axonal oxidant stress in the LC. Importantly, we also showed that Ab pathology was increased in APP/PS1 mice that underwent chronic, intermittent alcohol consumption compared to age-matched water drinking mice. Thus, we hypothesize that chronic, intermittent alcohol consumption decreases VMAT2 expression in the LC leading to increased metabolism of cytosolic norepinephrine by MAO, which then causes axonal mitochondrial oxidant stress. This elevated mitochondrial oxidant stress would then accelerate LC degeneration and Ab deposition in mouse models of AD. We will test this hypothesis using 2 genetic mouse models of AD, APP/PS1 and APP-NL knock- in mice, which develop progressive Ab pathology. A combination of cutting-edge two-photon laser scanning microscopy (2PLSM) in ex vivo brain slices, false fluorescent neurotransmitters (FFNs), genetically encoded redox biosensors, immunohistochemistry, stereological, pharmacological, and genetic techniques will be used to investigate the effects of chronic, intermittent alcohol consumption on VMAT2 expression, VMAT2 packaging of norepinephrine, LC axonal mitochondrial oxidant stress, LC degeneration, Ab pathology, and MAO-dependence.
In aim 1, we will determine the effect of chronic, intermittent alcohol consumption on LC axonal mitochondrial oxidant stress.
In aim 2, we will determine the effect of chronic alcohol consumption on LC degeneration and Ab pathology. Our proposed experiments will be the first to explore a novel axonal mitochondrial oxidant stress-mediated neurodegenerative mechanism underlying the interaction between chronic alcohol consumption and AD.

Public Health Relevance

Alcohol is the most commonly abused substance in the US and Alzheimer?s disease is the most common neurodegenerative disease; recent evidence indicates that alcohol abuse increases the risk for developing Alzheimer?s disease and accelerates disease trajectory. Our novel pilot studies indicated that chronic, intermittent alcohol consumption increased mitochondrial oxidant stress in locus coeruleus axons and increased Alzheimer?s related pathology in a mouse model of Alzheimer?s disease. Our proposal is aimed at understanding the effect of chronic, intermittent alcohol consumption on mitochondria in locus coeruleus neurons and how this impacts neurodegeneration and Alzheimer?s related pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG070962-01
Application #
10131479
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
2020-09-15
Project End
2025-06-30
Budget Start
2020-09-15
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455