Decreased AQP4 Expression Aggravates ɑ-Synuclein Pathology in Parkinson’s Disease Mice, Possibly via Impaired Glymphatic Clearance

Cui, Huili; Wang, Wenkang; Zheng, Xinhui; Xia, Danhao; Liu, Han; Qin, Chi; Tian, Haiyan; Teng, Junfang

doi:10.1007/s12031-021-01836-4

Cited by 59 publications

(46 citation statements)

References 53 publications

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“…A recent research from rodent middle cerebral artery occlusion (MCAO) models demonstrates that, although astrocytes are not as mobile as microglia, they are able to polarize their distal processes without migration of cell body and phagocytose apoptotic bodies derived from dendrites of dying neurons in the infarct core ( Damisah and Hill, 2020 ). What is more, a recent study demonstrated that decreased expression of astrocytic AQP4 accelerated deposition of α-synuclein and aggravated the loss of dopamine neurons via impairment of the GS ( Cui et al, 2021 ). The decreased expression of astrocytic AQP4 is also associated with reduced dendritic spine density of cortical neurons ( Venkat et al, 2017 ).…”

Section: Communication Between the Gs Cellular Componentsmentioning

confidence: 99%

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

Zhao

et al. 2021

Front. Aging Neurosci.

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The glymphatic system (GS) is a novel defined brain-wide perivascular transit network between cerebrospinal fluid (CSF) and interstitial solutes that facilitates the clearance of brain metabolic wastes. The complicated network of the GS consists of the periarterial CSF influx pathway, astrocytes-mediated convective transport of fluid and solutes supported by AQP4 water channels, and perivenous efflux pathway. Recent researches indicate that the GS dysfunction is associated with various neurological disorders, including traumatic brain injury, hydrocephalus, epilepsy, migraine, and Alzheimer’s disease (AD). Meanwhile, the GS also plays a pivotal role in the pathophysiological process of stroke, including brain edema, blood–brain barrier (BBB) disruption, immune cell infiltration, neuroinflammation, and neuronal apoptosis. In this review, we illustrated the key anatomical structures of the GS, the relationship between the GS and the meningeal lymphatic system, the interaction between the GS and the BBB, and the crosstalk between astrocytes and other GS cellular components. In addition, we contributed to the current knowledge about the role of the GS in the pathology of stroke and the role of AQP4 in stroke. We further discussed the potential use of the GS in early risk assessment, diagnostics, prognostics, and therapeutics of stroke.

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Section: Communication Between the Gs Cellular Componentsmentioning

confidence: 99%

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

Zhao

et al. 2021

Front. Aging Neurosci.

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“…Adding to these findings, the study also proposed a crucial role for the glymphatic system in the context of neurodegenerative disease in its clearance of cytotoxic waste products, namely amyloid-β, from the brain [ 49 ]. This was followed up by other studies, also implicating the clearance of tau from the brain by this pathway [ 48 , 50 ], and also α-synuclein [ 51 , 52 ]. Many additional studies have also shown that the astrocytic AQP4 is essential for fast glymphatic transport in different systems and disease models [ 48 , 62 – 67 ], further emphasizing the central role of astroglial cells in this CNS solute clearance system.…”

Section: Introductionmentioning

confidence: 80%

“…Greater research focus is required to address such hypotheses and understand the relationship between glymphatic function and α-synuclein, but a very recent publication has gone some way to unequivocally linking the two. Cui et al [ 52 ] showed that hemizygous AQP4 knockout mice which received a bi-lateral intrastriatal injection of α-synuclein pre-formed fibrils presented an accelerated pathologic deposition of α-synuclein, which in turn, facilitated the loss of dopaminergic neurons and consequent motor-behaviour impairments. Together, these findings further suggest that impaired glymphatic function, through decreased AQP4 expression, is capable of aggravating PD-like pathology in the brain, warranting further investigation of this pathway, or at least this water channel, as a therapeutic target in α-synucleinopathies.…”

Section: α-Synucleinmentioning

confidence: 99%

“…Acceleration of endogenous mechanisms which clear the extracellular ISF of these protein species could therefore potentially hold therapeutic promise against their propagation in the brain. Notably, the glymphatic pathway has been shown to have a critical influence on elimination of extracellular molecules, such as amyloid-β, tau and α-synuclein [ 48 – 52 ]. This pathway may thus have novel therapeutic potential against prion-like propagation in the raft of neurodegenerative disease states.…”

Section: Introductionmentioning

confidence: 99%

“…Controversy aside, the glymphatic system of fluid exchange in the brain has been shown to have a critical influence on clearance of the extracellular space and elimination of molecules prone to aggregation in neurodegenerative diseases, namely amyloid [ 49 ] and tau [ 48 , 50 ]. Like tau, α-synuclein also causes neuronal cell death through intracellular aggregation, and the neuron-to-neuron and region-to-region patterns of propagation of these proteins in the brain suggest that the extracellular space acts as an essential transport conduit for their spread [ 51 , 52 ]. As has been described above, age, and associated changes in neuroinflammation have been shown to alter glymphatic function [ 68 – 70 , 72 ].…”

Section: Introductionmentioning

confidence: 99%

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Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system

Lopes

Llewellyn

Harrison

2022

Transl Neurodegener

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Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system; however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined; however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.

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Glymphatic pathway: An emerging perspective in the pathophysiology of neurodegenerative diseases

Rehman,

Sehar,

Rasool

et al. 2024

Int J Geriat Psychiatry

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The central nervous system (CNS) is widely recognized as the only organ system without lymphatic capillaries to promote the removal of interstitial metabolic by‐products. Thus, the newly identified glymphatic system which provides a pseudolymphatic activity in the nervous system has been focus of latest research in neurosciences. Also, findings reported that, sleep stimulates the elimination actions of glymphatic system and is linked to normal brain homeostatis. The CNS is cleared of potentially hazardous compounds via the glymphatic system, particularly during sleep. Any age‐related alterations in brain functioning and pathophysiology of various neurodegenerative illnesses indicates the disturbance of the brain's glymphatic system. In this context, β‐amyloid as well as tau leaves the CNS through the glymphatic system, it's functioning and CSF discharge markedly altered in elderly brains as per many findings. Thus, glymphatic failure may have a potential mechanism which may be therapeutically targetable in several neurodegenerative and age‐associated cognitive diseases. Therefore, there is an urge to focus for more research into the connection among glymphatic system and several potential brain related diseases. Here, in our current review paper, we reviewed current research on the glymphatic system's involvement in a number of prevalent neurodegenerative and neuropsychiatric diseases and, we also discussed several therapeutic approaches, diet and life style modifications which might be used to acquire a more thorough performance and purpose of the glymphatic system to decipher novel prospects for clinical applicability for the management of these diseases.

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Decreased AQP4 Expression Aggravates ɑ-Synuclein Pathology in Parkinson’s Disease Mice, Possibly via Impaired Glymphatic Clearance

Cited by 59 publications

References 53 publications

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system

Glymphatic pathway: An emerging perspective in the pathophysiology of neurodegenerative diseases

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