Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease

Ciappelloni, Silvia; Bouchet, Delphine; Dubourdieu, Nadège; Boué‐Grabot, Éric; Kellermayer, Blanka; Manso, Constance; Marignier, Romain; Oliet, Stéphane H. R.; Tourdias, Thomas; Groc, Laurent

doi:10.1016/j.celrep.2019.05.097

Cited by 53 publications

(41 citation statements)

References 76 publications

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“…4). In mice, M1 or M23 splice variants can determine localization of AQP4, with higher levels of M23 at astrocytic endfeet 25,26 . Although we found no difference in intensity of the M1 or M23 bands between day and night ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Circadian control of brain glymphatic and lymphatic fluid flow

et al. 2020

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The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on timeof-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.

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Section: Resultsmentioning

confidence: 99%

Circadian control of brain glymphatic and lymphatic fluid flow

et al. 2020

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“…Deep cortex AQP4 expression, however, demonstrated signi cant increase within the late treatment group, more than doubling compared with controls. While the mechanisms of AQP4 regulation are not fully understood, osmotic stress has recently been linked to overall AQP4 expression (60)(61)(62).…”

Section: Deep Cortex Regionmentioning

confidence: 99%

Glial Associated Impairment of the Glymphatic System in Experimental Neonatal Hydrocephalus

Vasas¹,

McAllister²,

Eskandari³

2021

Preprint

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Background Changes in aquaporin-4 (AQP4) and glial fibrillary acid protein (GFAP) expression by astrocytes have been observed in several pathologies. It is hypothesized that prolonged exposure to pathologically elevated intracranial pressure (ICP) may be linked to impaired glymphatic pathways. In this study we explore histological consequences of prolonged pressure-induced injury in a feline model of neonatal hydrocephalus through changes in AQP4 and GFAP expression. We discuss the implications this may have in gaining a better understanding of the underlying mechanisms of hydrocephalus (HCP). Methods Using a neonatal feline model, obstructive HCP was induced through kaolin injection into the cisterna magna. Time between injection and intervention via ventricular reservoir placement was used to divide groups into early and late treatment groups. Early and late animals received reservoirs at 1- and 2-weeks post kaolin injection, respectively. Controls underwent sham operations (saline injection instead of kaolin). Animals were sacrificed at 4 months allowing for a chronic treated hydrocephalic model at time of brain harvest. Immunofluorescent staining for GFAP, AQP4 and DAPI was performed on histological brain sections from each group, and densitometry was used to quantify the relative signal of protein expression. Results Hydrocephalus was seen in all animals receiving kaolin injection as demonstrated by magnetic resonance imaging, clinical examination and neurological sequelae. Hydrocephalic animals demonstrated lower levels of perivascular AQP4 expression, increased diffuse AQP4 expression and increased glial scarring of perivascular, ependymal and subependymal spaces. Cerebral microvasculature of early treatment groups demonstrated increased astrocytic processes in the perivascular spaces, while late treatment groups demonstrated increased glial scar formation. Overall, the glymphatic system was severely disrupted in chronic treated hydrocephalus compared to controls. Conclusions Reactive astrogliosis and AQP4 mislocation are evident in early and late reservoir-treated HCP. Glial scarring in the perivascular, ependymal and subependymal spaces concurrent with AQP4 internalization from the perivascular region are prominent in HCP conditions present within the neonatal period. Delay in treatment by 1 week demonstrates quantifiable increases in perivascular and ependymal glial scarring at 4 months of age. Further investigation is needed to correlate glymphatic disruption with impaired CSF absorption and its role in promoting progressive hydrocephalus.

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“…AQP4 is the most abundant AQP in the brain, spinal cord and optic nerve (Potokar et al, 2016 ), is widely expressed on the plasma membranes of astrocytes with the highest concentration on perivascular end feet of astrocytes (Rosu et al, 2019 ). In the brain, AQP4 is primarily localized to the sub-pial astrocyte processes that form the glial-limiting membrane, the basolateral membrane of ependymal cells throughout the brain and spinal cord, and the perivascular astrocyte end feet that constitute a main component of the NVU (Hubbard et al, 2018 ; Ciappelloni et al, 2019 ; Dasdelen et al, 2019 ). AQP4 facilitates the flow of water into and out of the brain due its expression on cells that form barriers between the brain and major fluid compartments (Dasdelen et al, 2019 ).…”

Section: Aquaporins In the Nervous Systemmentioning

confidence: 99%

“…These data suggest that neuroinflammation is dependent, in part on AQP4 (Zhang et al, 2019 ). AQP4 is also the target antigen in the neurological autoimmune disease neuromyelitis spectrum disorder, which is an autoimmune astrocyte-specific cytopathy characterized by astrocyte loss, demyelination in the spinal cord, optic nerve and brain (Hinson et al, 2008 ; Sakalauskaite-Juodeikiene et al, 2018 ; Ciappelloni et al, 2019 ; Mader and Brimberg, 2019 ). Neuromyelitis spectrum disorder patients have chronic neuroinflammation leading to the classic presentations of this disease which include long segments of spinal cord inflammation, severe optic nerve inflammation, and area postrema syndrome (Huda et al, 2019 ).…”

Section: Aquaporins and Neuroinflammationmentioning

confidence: 99%

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

Tice¹,

McDevitt

Langford³

2020

Front. Cell. Infect. Microbiol.

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The discovery of the glial-lymphatic or glymphatic fluid clearance pathway in the rodent brain led researchers to search for a parallel system in humans and to question the implications of this pathway in neurodegenerative diseases. Magnetic resonance imaging studies revealed that several features of the glymphatic system may be present in humans. In both rodents and humans, this pathway promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF) through the arterial perivascular spaces into the brain parenchyma. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocytic end feet that abut cerebral endothelial cells of the blood brain barrier. Decreased expression or mislocalization of AQP4 from astrocytic end feet results in decreased interstitial flow, thereby, promoting accumulation of extracellular waste products like hyperphosphorylated Tau (pTau). Accumulation of pTau is a neuropathological hallmark in Alzheimer's disease (AD) and is accompanied by mislocalization of APQ4 from astrocyte end feet to the cell body. HIV infection shares many neuropathological characteristics with AD. Similar to AD, HIV infection of the CNS contributes to abnormal aging with altered AQP4 localization, accumulation of pTau and chronic neuroinflammation. Up to 30% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), and changes in AQP4 may be clinically important as a contributor to cognitive disturbances. In this review, we provide an overview and discussion of the potential contributions of NeuroHIV to glymphatic system functions by focusing on astrocytes and AQP4. Although HAND encompasses a wide range of neurocognitive impairments and levels of neuroinflammation vary among and within PWH, the potential contribution of disruption in AQP4 may be clinically important in some cases. In this review we discuss implications for possible AQP4 disruption on NeuroHIV disease trajectory and how HIV may influence AQP4 function.

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Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease

Cited by 53 publications

References 76 publications

Circadian control of brain glymphatic and lymphatic fluid flow

Circadian control of brain glymphatic and lymphatic fluid flow

Glial Associated Impairment of the Glymphatic System in Experimental Neonatal Hydrocephalus

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

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