Project Details
Description
PROJECT SUMMARY
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.
Status | Active |
---|---|
Effective start/end date | 9/15/20 → 6/30/24 |
Funding
- National Institute on Aging: $387,500.00
- National Institute on Aging: $385,000.00
- National Institute on Aging: $387,500.00
- National Institute on Aging: $387,500.00
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