Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden

Abstract

The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.

Mechanisms of Association of Sleep and Metabolic Syndrome

“…6) On the other hand, higher levels of β amyloid protein might lead to sleep fragmentation, a worsening of sleep quality and daytime somnolence. Concentration will be more difficult, and performance will be reduced [24,36,[41][42][43][44]. Similarly, higher levels of abnormal tau proteins may interfere with the sleep-wake cycle [45,23].…”

Biomarkers of dementia in obstructive sleep apnea

“…This gene codes for a water channel involved in the clearance of products via the so-called glymphatic system. AQP4 polymorphisms modified the rate of cognitive decline after AD diagnosis in one study, and moderated the relationship between sleep quality and Aβ burden measured with PET imaging in another [35,36]. In the context of recent discoveries linking sleep quality to Aβ clearance in the interstitial fluid [22], more studies are needed to better define how AQP4 polymorphisms are involved in the relationship between sleep disruption and the incidence of dementia.…”

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

“…Interestingly, a recent study reported that a single nucleotide polymorphism (SNP) in AQP4, rs72878776, is associated with altered overall sleep quality according to the Pittsburgh Sleep Quality Index (PSQI) sleep parameters such as sleep latency, comfort, and difficulty falling asleep (Rainey-Smith et al, 2018 ). Individuals that are homozygous for the AQP4 rs72878776-A (0.001% of the population) allele reported worse overall sleep compared to those with a different genotype (Rainey-Smith et al, 2018 ).…”

“…Interestingly, a recent study reported that a single nucleotide polymorphism (SNP) in AQP4, rs72878776, is associated with altered overall sleep quality according to the Pittsburgh Sleep Quality Index (PSQI) sleep parameters such as sleep latency, comfort, and difficulty falling asleep (Rainey-Smith et al, 2018 ). Individuals that are homozygous for the AQP4 rs72878776-A (0.001% of the population) allele reported worse overall sleep compared to those with a different genotype (Rainey-Smith et al, 2018 ). This SNP is in the 5-prime untranslated region (5′UTR) of the AQP4 gene and may be of functional relevance through potentially influencing gene transcription, via modification (creation or deletion) of transcription factor binding sites (Rainey-Smith et al, 2018 ).…”

“…Thus, it stands to reason that aging is a major risk factor for developing a neurodegenerative disease, many of which are characterized by accumulation of aberrant proteins, such as hyperphosphorylated Tau (pTau). In this context, decreased glymphatic clearance may increase the risk of neurodegenerative changes contributing to cognitive decline in the aging population or in age-related CNS diseases (Rainey-Smith et al, 2018 ). For example, during aging, cerebral arterial walls begin to stiffen and prevent smooth arterial pulses needed for CSF influx and ISF exchange (Badaut et al, 2014 ; Sweeney et al, 2019 ).…”