Alcohol Use Disorder, Neurodegeneration, Alzheimer's and Parkinson's Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Abstract

Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer's and Parkinson's disease.

Keywords: Alzheimer; Parkinson; alcohol; excitotoxicity; neurodegeneration; neuroimmune; neuroinflammation; oxidative.

FIGURE 1

The crosstalk between peripheral and central immune system in Alcohol Use Disorder (AUD) leading to cell death. Alcohol consumption increases the peripheral production of reactive oxygen species (ROS), Toll-like receptor 4 (TLR4), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and inflammatory cytokines, which cross the blood brain barrier (BBB). At central nervous system, alcohol induces neuroinflammation that potentially leads to apoptosis or neurosis. Alcohol stimulates more B-cell lymphoma-2-associated X (BAX) formation, Caspase 3 expression and activates Glycogen synthase kinase-3 β (GSK3β) by reducing its Serine 9 phosphorylation. GSK3β also directly phosphorylates BAX leading to neuronal apoptosis. Alcohol stimulates neuronal release of HMGB1 and TLR4 expression on microglia, astrocytes and neurons. HMGB1-TLR4 interaction activates microglia into; M1 phenotye (anti-inflammatory) during 1st alcohol intake, and M2 phenotype (pro-inflammatory) in subsequent alcohol exposure. M2 phenotype and astrocytes releases several pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin 1 Beta (IL-1β), interleukin-6 (IL-6), NF-κB and monocyte chemoattractant protein-1 (MCP1). Alcohol stimulates ROS production by increasing NADPH-dependent oxidase (NOX), NOXgp91^phox expression and activity, leading to oxidative stress. Collectively alcohol-induced neuroinflammation and oxidative stress causes neuronal death via apoptosis and necrosis pathways.

FIGURE 2

Alcohol-excitotoxicity induced cell death through glutamate and glucocorticoids. Chronic alcohol consumption damages astrocyte and its ability to regulate extracellular glutamate concentration, leading to hyperglutamatergic excitotoxicity. Chronic alcohol consumption increases glucocorticoids level, further elevating extracellular glutamate concentration. Alcohol-induced glucocorticoids also worsen alcohol-excitotoxicity induced cell death by increasing N-Methyl-D-aspartate receptors (NMDARs) and its subunit expression, NR2A and NR2B. NMDARs overactivation causes calcium influx and causes cardiolipin translocation, leading to B-cell lymphoma-2-associated X (BAX) pore formation on mitochondria, which releases cytochrome c causing neuronal cell death.

FIGURE 3

Potential association between Alcohol Use Disorder and manifestation of Alzheimer’s disease (AD). Chronic alcohol intake triggers oxidative stress, increases amyloid precursor protein (APP), presenilin (PS1) and nicastrin expression that serves as a basis for amyloid β (aβ) production and aβ aggregates. Chronic alcohol intake reduces phosphorylation of proteins associated with mTOR/AKT pathway and increases total tau expression. Chronic alcohol activates CDK5 and Glycogen synthase kinase-3 β (GSK3β) and hyperphosphorylates Tau protein into Tau tangles. Aggregates of aβ directly causes neurodenegeration and also through tau tangles. Hyperphosphorylation of tau proteins results in loss of microtubule stability, causing neurodegeneration.

FIGURE 4

Potential association between Alcohol Use Disorder and development of Parkinson’s disease (PD). Increase in α-synuclein production and nigrostriatal dopaminergic neurodegeneration contribute to Parkinson’s disease (PD) progression. At early stage of AUD, alcohol consumption transiently increases vesicular monoamine transporter (VMAT2) activity and dopamine release in nigrostriatal reward pathway. Chronic binge alcohol intake exhausts dopamine content and consequently reducing VMAT2 activity in striatal neurons (caudate putamen and nucleus). Increased expression of α-synuclein in AUD also restricts the release of dopaminergic synaptic vesicles via reduced (VMAT2) activity. Chronic alcohol intake causes α-synuclein aggregation, leading to formation of Lewy bodies, which eventually results in degeneration of dopaminergic neurons at substantia niagra.