Haplotype of the astrocytic water channel AQP4 modulates slow wave energy in human NREM sleep

Abstract

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid-eye-movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG-recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep and cognitive consequences of prolonged wakefulness.

The Role of the Circadian System in Attention Deficit Hyperactivity Disorder

“…Genetic variations in the water-channel protein aquaporin-4 (AQP4), expressed in astrocytic end-feet, in cognitively normal older adults, however, were associated with disrupted self-reported sleep quality (Pittsburgh Sleep Quality Index, PSQI) and found to moderate the coupling between sleep latency/duration and PET Aβ burden (Rainey- Brown et al 2016). Given the implication of AQP4 in glymphatic transport , as well as the modulatory effect of AQP4-haplotype on NREM slow-wave energy (Larsen et al 2019), these results support the notion of paravascular clearance of Aβ and suggest that genetic variations in AQP4 modulate the efficacy of this process. SD was also observed to increase CSF tau by over half in a human cohort with changes in phosphorylation being highly site-specific (Barthelemy et al 2020).…”

The Reciprocal Interaction Between Sleep and Alzheimer’s Disease

“…Genetic variations in the water-channel protein aquaporin-4 (AQP4), expressed in astrocytic end-feet, in cognitively normal older adults, however, were associated with disrupted self-reported sleep quality (Pittsburgh Sleep Quality Index, PSQI) and found to moderate the coupling between sleep latency/duration and PET Aβ burden (Rainey-Smith et al 2018;Brown et al 2016). Given the implication of AQP4 in glymphatic transport (Mestre et al 2018), as well as the modulatory effect of AQP4-haplotype on NREM slow wave energy (Larsen et al 2019), these results…”

Brain Glymphatic/Lymphatic Imaging by MRI and PET

“…8d). AD had been associated with sleep problems, and sleep disorder-related clearance dysfunction was revealed, and the possibility of prevention of AD by controlling sleep pattern was raised [46,66,74,79,118] (Fig. 6c).…”