Abstract
Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration.
Highlights
Alcohol, being widely-used in human societies, is one of the most well-known neurotoxic agents, since long-term heavy consumption of alcohol causes injury to many tissues including liver, pancreas, brain, etc [1]
We first investigated the respective distribution of AGE and albumin in the brains of human alcoholics and normal individuals to study the mechanisms by which AGE-albumin was increased and how it promoted neuronal cell death
By using immunoblot and mass-spectromeal analyses, we have reported that albumin is synthesized in microglial cells of the brain [34]
Summary
Alcohol (ethanol), being widely-used in human societies, is one of the most well-known neurotoxic agents, since long-term heavy consumption of alcohol causes injury to many tissues including liver, pancreas, brain, etc [1]. Heavy alcohol ingestion promotes abnormal behavior and disorders of the central nervous system [2,3,4]. Alcohol consumption induces neuroinflammation, which activates microglia. These regions of alcoholic brain injury display elevated appearance of activated microglial cells [11,12,13,14]. The relationship between alcohol consumption and microglial activation has long been studied, but their pathological roles have been poorly established [15,16,17,18]
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