Defining novel functions for cerebrospinal fluid in ALS pathophysiology

Kwong, Koy Chong Ng Kee; Mehta, Arpan R.; Chandran, Siddharthan

doi:10.1186/s40478-020-01018-0

Cited by 23 publications

(15 citation statements)

References 225 publications

(275 reference statements)

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“…In some versions of the glymphatic hypothesis the perivenous outflow is thought to enter the subarachnoid spaces where it mixes with CSF (e.g. [ 36 , 76 , 90 , 91 ]. These versions can easily be modified and extended to include outflow via white matter tracts leading to the ventricles [ 60 , 64 , 92 ].…”

Section: The Development Of the Glymphatic Hypothesismentioning

confidence: 99%

The glymphatic hypothesis: the theory and the evidence

Hladky

Barrand

2022

Fluids Barriers CNS

142

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The glymphatic hypothesis proposes a mechanism for extravascular transport into and out of the brain of hydrophilic solutes unable to cross the blood–brain barrier. It suggests that there is a circulation of fluid carrying solutes inwards via periarterial routes, through the interstitium and outwards via perivenous routes. This review critically analyses the evidence surrounding the mechanisms involved in each of these stages. There is good evidence that both influx and efflux of solutes occur along periarterial routes but no evidence that the principal route of outflow is perivenous. Furthermore, periarterial inflow of fluid is unlikely to be adequate to provide the outflow that would be needed to account for solute efflux. A tenet of the hypothesis is that flow sweeps solutes through the parenchyma. However, the velocity of any possible circulatory flow within the interstitium is too small compared to diffusion to provide effective solute movement. By comparison the earlier classical hypothesis describing extravascular transport proposed fluid entry into the parenchyma across the blood–brain barrier, solute movements within the parenchyma by diffusion, and solute efflux partly by diffusion near brain surfaces and partly carried by flow along “preferred routes” including perivascular spaces, white matter tracts and subependymal spaces. It did not suggest fluid entry via periarterial routes. Evidence is still incomplete concerning the routes and fate of solutes leaving the brain. A large proportion of the solutes eliminated from the parenchyma go to lymph nodes before reaching blood but the proportions delivered directly to lymph or indirectly via CSF which then enters lymph are as yet unclear. In addition, still not understood is why and how the absence of AQP4 which is normally highly expressed on glial endfeet lining periarterial and perivenous routes reduces rates of solute elimination from the parenchyma and of solute delivery to it from remote sites of injection. Neither the glymphatic hypothesis nor the earlier classical hypothesis adequately explain how solutes and fluid move into, through and out of the brain parenchyma. Features of a more complete description are discussed. All aspects of extravascular transport require further study.

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Section: The Development Of the Glymphatic Hypothesismentioning

confidence: 99%

The glymphatic hypothesis: the theory and the evidence

Hladky

Barrand

2022

Fluids Barriers CNS

142

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“…Of note is the possibility already suggested by others that the CSF circulation could constitute a pathway for the spread of pathology, which various lines of evidence are now hinting at ( Smith et al, 2015 ; Gomez-Pinedo et al, 2018 ; Mishra et al, 2020 ). This could in turn help to potentially account for many of the unexplained features of ALS, one of which is the non-contiguous spreading pattern occasionally observed ( Smith et al, 2015 ; Ng Kee Kwong et al, 2020b ).…”

Section: Als As a Proteinopathymentioning

confidence: 99%

40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Kwong

Harbham

Selvaraj

et al. 2021

Front. Mol. Neurosci.

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Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.

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“…48 The abnormal expression of AQP4 has been associated with altered blood-brain barrier integrity in ALS sufferers, as well as impaired potassium homeostasis and glutamate dysregulation. 76,77 Based on these observations, we examined the expression of both KCNJ10 and AQP4 in human iPSC-derived VS astrocytes. We observed that these preparations express low levels of AQP4, suggesting that they should be suited to investigate the functional impact of AQP4 up-regulation, a situation that would be expected in astrocytes generated from iPSCs derived from ALS patients.…”

Section: Human Ipsc-derived Ventral Spinal-like Astrocytes Have Properties Of Physiological Astrocytesmentioning

confidence: 99%

Rapid generation of ventral spinal cord-like astrocytes from human iPSCs for modeling non-cell autonomous mechanisms of lower motor neuron disease

Soubannier

Chaineau

Gursu

et al. 2021

Preprint

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BackgroundAstrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human induced pluripotent stem cell (iPSC)-based approaches are becoming increasingly important for the study of the mechanisms underlying the involvement of astrocytes in non-cell autonomous processes of motor neuron degeneration in ALS. These studies must account for the molecular and functional diversity among astrocytes in different regions of the brain and spinal cord. It is essential that the most pathologically-relevant astrocyte preparations are used when investigating non-cell autonomous mechanisms of either upper or lower motor neuron degeneration in ALS. In this context, the main aim of this study was to establish conditions enabling rapid and robust generation of physiologically-relevant ventral spinal cord-like astrocytes that would provide an enhanced experimental model for the study of lower motor neuron degeneration in ALS.MethodsNeural progenitor cells with validated caudal and ventral features were derived from human iPSCs and differentiated into astrocytes, which were then characterized by examining morphology, markers of ventral spinal cord astrocytes, spontaneous and induced calcium transients, and astrogliosis markers.ResultsEfficient and streamlined generation of human iPSC-derived astrocytes with molecular and biological properties similar to physiological astrocytes in the ventral spinal cord was achieved. These induced astrocytes express markers of mature ventral spinal cord astrocytes, exhibit spontaneous and ATP-induced calcium transients, and lack signs of overt activation.ConclusionsHuman iPSC-derived astrocytes with ventral spinal features offer advantages over ‘generic’ astrocyte preparations for the study of both ventral spinal cord astrocyte biology and the involvement of astrocytes in mechanisms of lower motor neuron degeneration in ALS.

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Defining novel functions for cerebrospinal fluid in ALS pathophysiology

Cited by 23 publications

References 225 publications

The glymphatic hypothesis: the theory and the evidence

The glymphatic hypothesis: the theory and the evidence

40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Rapid generation of ventral spinal cord-like astrocytes from human iPSCs for modeling non-cell autonomous mechanisms of lower motor neuron disease

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