Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis

Watanabe-Matsumoto, Saori; Moriwaki, Yuji; Okuda, Takashi; Ohara, Shuichi; Yamanaka, Koji; Abe, Yoichiro; Yasui, Masato; Misawa, Hidemi

doi:10.1016/j.neures.2017.11.001

Cited by 24 publications

(23 citation statements)

References 45 publications

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“…There is further proof that even the substantial disruption of the BSCB that follows NF-κB activation in astrocytes is not necessarily associated with a worsening of the disease progression ( Ouali Alami et al, 2018 ). Furthermore, mutant SOD1 mice lacking aquaporin-4 display an intact BSCB but do not have a better disease course and survival ( Watanabe-Matsumoto et al, 2018 ). Our data show that the activation of D(Gi) in astrocytes restores BSCB integrity without ameliorating the burden of multiple disease markers in MN (effectively dissociating the BSCB from other disease manifestations).…”

Section: Discussionmentioning

confidence: 99%

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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Blood–spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1G93A, FUSΔNLS, TDP43G298S, and Tbk1+/− ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1G93A mice to demonstrate that the BSCB is rescued by increased MN firing, whereas inactivation worsens it. Moreover, we use DREADD chemogenetics, alone or in multiplexed form, to show that activation of Gi signaling in astrocytes restores BSCB integrity, independently of MN firing, with no effect on MN disease markers and dissociating them from BSCB disruption. We show that astrocytic levels of the BSCB stabilizers Wnt7a and Wnt5a are decreased in SOD1G93A mice and strongly enhanced by Gi signaling, although further decreased by MN inactivation. Thus, we demonstrate that BSCB impairment follows MN dysfunction in ALS pathogenesis but can be reversed by Gi-induced expression of astrocytic Wnt5a/7a.

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Section: Discussionmentioning

confidence: 99%

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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“…Also, much attention has been paid on glymphatic system [87] and intramural peri-arterial drainage pathway [88], by which misfolded/aggregated proteins in interstitial fluid (ISF) of the brain and spinal cord could be drained into cerebrospinal fluid (CSF) and then cleared [89]. Regarding SOD1-ALS, indeed, the disease duration of transgenic mice expressing ALS-linked mutant SOD1 was shortened by deletion of aquaporin-4 [90], a water channel playing central roles in the extracellular clearance through the glymphatic system [87]. Furthermore, pathologies and amyloid-β accumulation in transgenic mouse models of Alzheimer's disease were aggravated by disrupting meningeal lymphatic vessels, which are proposed as a drain of macromolecules from ISF and CSF [91].…”

Section: Misfolded Forms Of Sod1 In Cerebrospinal Fluid Of Alsmentioning

confidence: 99%

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Furukawa

Tokuda

2020

Transl Neurodegener

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Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.

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“…The bidirectional water channel aquaporin 4 (AQP4) is widely distributed in the plasma membrane and maintains the tissue microenvironment by supporting molecular transfer between extracellular and intracellular spaces [1–3]. Although the vulnerability or advantages of its deficiency in neural tissue have been reported under pathological conditions [4–8], its physiological function is not fully understood [9].…”

Section: Introductionmentioning

confidence: 99%

Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina

et al. 2019

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The bidirectional water channel aquaporin 4 (AQP4) is abundantly expressed in the neural tissue. The advantages and disadvantages of AQP4 neural tissue deficiency under pathological conditions, such as inflammation, and relationship with neural diseases, such as Alzheimer’s disease, have been previously reported. However, the physiological functions of AQP4 are not fully understood. Here, we evaluated the role of AQP4 in the mouse retina using Aqp4 knockout (KO) mice. Aqp4 was expressed in Müller glial cells surrounding the synaptic area between photoreceptors and bipolar cells. Both scotopic and photopic electroretinograms showed hyperactive visual responses in KO mice, gradually progressing with age. Moreover, the amplitude reduction after frequent stimuli and synaptic fatigue was more severe in KO mice. Glutamine synthetase, glutamate aspartate transporter, synaptophysin, and the inward potassium channel Kir2.1, but not Kir4.1, were downregulated in KO retinas. KIR2.1 colocalized with AQP4 in Müller glial cells at the synaptic area, and its expression was affected by Aqp4 levels in primary Müller glial cell cultures. Intraocular injection of potassium in wild-type mice led to visual function hyperactivity, as observed in Aqp4 KO mice. Mitochondria molecules, such as Pgc1α and CoxIV, were downregulated, while apoptotic markers were upregulated in KO retinas. AQP4 may fine-tune synaptic activity, most likely by regulating potassium metabolism, at least in part, via collaborating with KIR2.1, and possibly indirectly regulating glutamate kinetics, to inhibit neural hyperactivity and synaptic fatigue which finally affect mitochondria and cause neurodegeneration.Electronic supplementary materialThe online version of this article (10.1007/s12035-019-01661-2) contains supplementary material, which is available to authorized users.

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Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis

Cited by 24 publications

References 45 publications

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina

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