Role of Alcohol Drinking in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Abstract

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against β-amyloid (Aβ) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of Aβ and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (CYP2E1) and an increase in the amount of α-Synuclein (αSYN) relevant to PD. The findings on the association between alcohol consumption and ALS are inconsistent; a recent population-based study suggests that alcohol drinking seems to not influence the risk of developing ALS. Additional research is needed to clarify the potential etiological involvement of alcohol intake in causing or resulting in major neurodegenerative diseases, which will eventually lead to potential therapeutics against these alcoholic neurodegenerative diseases.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Parkinson’s disease; alcohol; neurodegenerative diseases.

Figure 1

The harmful effects and mechanisms of alcohol. Chronic and excessive alcohol consumption alters gut microbiota, increases intestinal permeability (leaky gut) and causes brain damage. Lipopolysaccharide (LPS) and peptidoglycan (PGN) from the gut lumen to the systemic circulation are recognized by toll-like receptors (TLRs) expressed by immune cells and induce structural plasticity changes such as ionized calcium-binding adapter molecule 1 (IBA1) and glial fibrillary acidic protein (GFAP), as well as an inflammatory response by the nuclear factor-ĸB (NF-ĸB) pathway. The inflammatory cytokines and mediators, such as interleukin 4 (IL-4), IL-10, reactive oxygen species (ROS), inducible NO synthase (iNOS), IL-1β, IL-6, tumor necrosis factor (TNF)-α, C-C Motif Chemokine Ligand 2 (CCL2) and cyclooxygenase-2 (COX-2) may result in altered neuronal functions and angiogenesis.

Figure 2

Dual roles of alcohol drinking in Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). In AD, low or moderate concentrations of ethanol protect against the damage induced by Aβ. Excessive amounts of ethanol increase accumulation of Aβ and Tau phosphorylation [35]. In PD, most studies show that alcohol decreases levels of DA and increases the levels of αSYN. One study suggested that the high drinking alko alcohol (AA) rats showed lower stimulated DA levels and more efficient DA re-uptake in the nucleus accumbens core than the low drinking non-alcohol (ANA) rats did. In the same structure, AA rats also had significantly higher levels of α-syn. No differences were found in the effects of two different doses of ethanol (0.1 and 3.0 g/kg) [42]. A meta-analysis concluded that beer, but not wine and liquor, probably protected against PD [36]. In ALS, red wine extract intake was reported to prolong the lifespan of mSOD1-transgenic mice and protected neurons from apoptosis in vitro. There is a dysfunction of the glutamatergic excitatory system in ALS, and chronic alcohol intake involves changes in glutamatergic transmission. The association between alcohol and ALS is still unclear. Abbreviations: Aβ: β-amyloid; DA: Dopamine; mSOD1: Mutated SOD1.