The potential role of aryl hydrocarbon receptor in Alzheimer's disease: Protective or detrimental

Alzheimer's disease (AD) is the main cause of dementia in the old-age population worldwide. AD is a progressive brain neurodegenerative disease due to genetic and environmental factors that induce the accumulation of intracellular hyperphosphorylated tau protein and extracellular amyloid protein (Aβ). Particularly, cholinergic neurons in the prefrontal cortex and hippocampus are mainly affected in AD, resulting in cognitive impairment and memory dysfunction. Therefore, restoration of cholinergic neurotransmission by cholinergic agonists such as tacrine and donepezil could be effective in the management of AD. However, anti-AD medications cannot reverse the fundamental AD neuropathology. Therefore, targeting other pathways might be reasonable in the management of AD. Interestingly, aryl hydrocarbon receptors (AHRs), which are sensors for xenobiotics and enterobiotics, are involved in age-related neurodegeneration. It has been shown that AHRs have detrimental effects on AD neuropathology by disruption of BBB integrity and induction of cognitive impairment. Conversely, activation of brain AHRs by tryptophan attenuates the inflammatory reactions in AD. These findings emphasized the controversial roles of AHRs in the pathogenesis of AD. Therefore, this review discusses the exact role of AHRs in AD regarding the molecular mechanisms and related signaling pathways.