Aryl hydrocarbon receptor impairs circadian regulation in Alzheimer's disease: Potential impact on glymphatic system dysfunction

Jun 26, 2024The European journal of neuroscience

Aryl hydrocarbon receptor may disrupt daily rhythms and waste clearance in Alzheimer's disease

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Abstract

The expression of the aryl hydrocarbon receptor (AhR) is robustly increased in the brains of Alzheimer's patients.

Circadian clocks regulate the sleep-wake cycle and metabolic processes over a 24-hour period.
Impairment of circadian regulation is associated with Alzheimer's disease.
AhR activation may inhibit the expression of core clock proteins critical for maintaining circadian rhythms.
Increased AhR levels in the brain could disrupt the integrity of the blood-brain barrier.
AhR signaling may impair glymphatic flow, which is essential for waste clearance from the brain.
Neuroinflammation and changes in gut microbiota can activate AhR, potentially affecting both circadian functions and glymphatic flow.

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Circadian clocks maintain diurnal rhythms of sleep-wake cycle of 24 h that regulate not only the metabolism of an organism but also many other periodical processes. There is substantial evidence that circadian regulation is impaired in Alzheimer's disease. Circadian clocks regulate many properties known to be disturbed in Alzheimer's patients, such as the integrity of the blood-brain barrier (BBB) as well as the diurnal glymphatic flow that controls waste clearance from the brain. Interestingly, an evolutionarily conserved transcription factor, that is, aryl hydrocarbon receptor (AhR), impairs the function of the core clock proteins and thus could disturb diurnal rhythmicity in the BBB. There is abundant evidence that the activation of AhR signalling inhibits the expression of the major core clock proteins, such as the brain and muscle arnt-like 1 (BMAL1), clock circadian regulator (CLOCK) and period circadian regulator 1 (PER1) in different experimental models. The expression of AhR is robustly increased in the brains of Alzheimer's patients, and protein level is enriched in astrocytes of the BBB. It seems that AhR signalling inhibits glymphatic flow since it is known that (i) activation of AhR impairs the function of the BBB, which is cooperatively interconnected with the glymphatic system in the brain, and (ii) neuroinflammation and dysbiosis of gut microbiota generate potent activators of AhR, which are able to impair glymphatic flow. I will examine current evidence indicating that activation of AhR signalling could disturb circadian functions of the BBB and impair glymphatic flow and thus be involved in the development of Alzheimer's pathology.

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Aryl hydrocarbon receptor impairs circadian regulation in Alzheimer's disease: Potential impact on glymphatic system dysfunction

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