Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models

Abstract

Alzheimer’s disease (AD) is characterized by genetic and multifactorial risk factors. Many studies correlate AD to sleep disorders. In this study, we performed and validated a mouse model of AD and sleep fragmentation, which properly mimics a real condition of intermittent awakening. We noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to aquaporin-4 (AQP4) modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects aquaporin-4 channel (AQP4) expression according to the stage of the disease, with an up-regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4. Nevertheless, an in-depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms.

Novel murine closed-loop auditory stimulation paradigm elicits macrostructural sleep benefits in neurodegeneration

“…AD mice present heightened NREM sleep fragmentation accompanied by a decrease in NREM sleep duration compared to WT animals (Kollarik et al, 2022). Increased sleep fragmentation is a distinctive feature of neurodegenerative diseases, being linked to accelerated microglia and astrocyte aging and activation, cognitive impairment in patients, increasing amyloid-beta deposition, tau phosphorylation and neuroinflammation, and decreasing AQP4 expression in older AD animals (Cai et al, 2019;Kaneshwaran et al, 2019;Vasciaveo et al, 2023). Consequently, sleep alterations are clinical hallmarks that appear as crucial risk factors in neurodegeneration, and should be explored as therapeutic targets to control disease progression.…”

“…The copyright holder for this this version posted February 12, 2024. ; https://doi.org/10.1101/2024.02.12.579922 doi: bioRxiv preprint activation, cognitive impairment in patients, increasing amyloid-beta deposition, tau phosphorylation and neuroinflammation, and decreasing AQP4 expression in older AD animals (Cai et al, 2019;Kaneshwaran et al, 2019;Vasciaveo et al, 2023). Consequently, sleep alterations are clinical hallmarks that appear as crucial risk factors in neurodegeneration, and should be explored as therapeutic targets to control disease progression.…”

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…Aquaporin 4 (AQP4) is the major AQP found in the brain where it plays a significant role in water homeostasis. Current research has established that diminished AQP4 expression leads to reduced Aβ clearance and causes Aβ accumulation, leading to deficiencies in memory and learning ability and the development of CI ( Hubbard et al, 2018 ; Chandra et al, 2021 ; Fang et al, 2021 ; Liu et al, 2022 ; Wang et al, 2022 ; Vasciaveo et al, 2023 ). In addition to regulating water homeostasis, AQP4 also activates astrocytes ( Yang et al, 2022 ; Liu et al, 2023 ), and outside of the brain, it is expressed by IHCs ( Christensen et al, 2009 ; Nishio et al, 2013 ).…”

Emergence of the brain-border immune niches and their contribution to the development of neurodegenerative diseases

“…Perivascular spaces are established between tight junctions of the vascular endothelium and the astrocytic end feet and contain interstitial fluid from the outflow of blood from vessels, and CSF from the subarachnoid space. Although small in diameter, perivascular spaces together form an extensive network of glymphatic channels that function to drain CSF from the subarachnoid space ( 40 ) and remove neurometabolic waste from the brain, particularly during sleep ( 49 , 50 ).…”