Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses

Zhao, Fei; Deng, Jiangshan; Xu, Xiaofeng; Cao, Fengya; Lu, Kaili; Li, Dawei; Cheng, Xiaojuan; Wang, Xiuzhe; Zhao, Yuwu

doi:10.1186/s12974-018-1203-8

Cited by 43 publications

(29 citation statements)

References 49 publications

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“…Our data indicate that this upregulation of Aqp-4 is amplified in the SHRSP/FAD rat. A positive correlation between Aqp-4 and GFAP protein levels are consistent with prior reports of increased Aqp-4 corresponding with increased gliosis in a model of hypoglycemia (Zhao et al, 2018). Aqp-4 staining was redistributed to the neuropil, but it was unclear whether the loss of polarization was due to disintegration of vessels or retraction of endfeet.…”

Section: Discussionsupporting

confidence: 91%

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

Denver

D'Adamo

et al. 2019

Front. Physiol.

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Alzheimer's disease (AD) and mixed dementia (MxD) comprise the majority of dementia cases in the growing global aging population. MxD describes the coexistence of AD pathology with vascular pathology, including cerebral small vessel disease (SVD). Cardiovascular disease increases risk for AD and MxD, but mechanistic synergisms between the coexisting pathologies affecting dementia risk, progression and the ultimate clinical manifestations remain elusive. To explore the additive or synergistic interactions between AD and chronic hypertension, we developed a rat model of MxD, produced by breeding APPswe/PS1 E9 transgenes into the stroke-prone spontaneously hypertensive rat (SHRSP) background, resulting in the SHRSP/FAD model and three control groups (FAD, SHRSP and non-hypertensive WKY rats, n = 8-11, both sexes, 16-18 months of age). After behavioral testing, rats were euthanized, and tissue assessed for vascular, neuroinflammatory and AD pathology. Hypertension was preserved in the SHRSP/FAD cross. Results showed that SHRSP increased FAD-dependent neuroinflammation (microglia and astrocytes) and tau pathology, but plaque pathology changes were subtle, including fewer plaques with compact cores and slightly reduced plaque burden. Evidence for vascular pathology included a change in the distribution of astrocytic end-foot protein aquaporin-4, normally distributed in microvessels, but in SHRSP/FAD rats largely dissociated from vessels, appearing disorganized or redistributed into neuropil. Other evidence of SVD-like pathology included increased collagen IV staining in cerebral vessels and PECAM1 levels. We identified a plasma biomarker in SHRSP/FAD rats that was the only group to show increased Aqp-4 in plasma exosomes. Evidence of neuron damage in SHRSP/FAD rats included increased caspase-cleaved actin, loss of myelin and reduced calbindin staining in neurons. Further, there were mitochondrial deficits specific to SHRSP/FAD, notably the loss of complex II, accompanying FADdependent loss of mitochondrial complex I. Cognitive deficits exhibited by FAD rats were not exacerbated by the introduction of the SHRSP phenotype, nor was

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Section: Discussionsupporting

confidence: 91%

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

Denver

D'Adamo

et al. 2019

Front. Physiol.

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“…Quite remarkably, these AQP4-null mice show substantially improved outcomes and survivability over their wild-type counterparts in four models of CNS injury: ischemic stroke (Manley et al, 2000;Yao et al, 2015A;Hirt et al, 2017), water intoxication (Manley et al, 2000), bacterial meningitis (Papadopoulos and Verkman 2005), and spinal-cord compression (Saadoun et al, 2008). AQP4-null mice have also shown reduced CE and BBB permeability in a model of severe hypoglycemia (Zhao et al, 2018). These studies represent a genetic proof-of-principle highlighting the central role of AQP4 in the formation of cerebral edema and its potential as a target for an anti-edema strategy aimed at stroke therapy.…”

Section: Introductionmentioning

confidence: 96%

Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury

et al. 2019

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Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet. Using AQP4-expressing cells, we screened small molecule libraries for inhibitors that reduce AQP4-mediated water permeability. Additional functional assays were used to validate AQP4 inhibition and identified a promising structural series for medicinal chemistry. These efforts improved potency and revealed a compound we designated AER-270, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. AER-270 and a prodrug with enhanced solubility, AER-271 2-{[3,5-Bis(trifluoromethyl)

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“…AQP4 is abundantly expressed in astrocytic endfeet processes in direct contact with blood vessels 7‐9 . The specific highly polarized expression of AQP4 was suggested to play critical roles in maintaining cerebral water balance and BBB integrity 10‐13 . Previous studies have reported that AQP4 polarity was disturbed in various neurological diseases that cause brain edema and BBB disruption 14‐17 .…”

Section: Introductionmentioning

confidence: 99%

Poldip2 mediates blood‐brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model

Gao

Shu

et al. 2020

CNS Neurosci Ther

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Background Specific highly polarized aquaporin‐4 (AQP4) expression is reported to play a crucial role in blood‐brain barrier (BBB) integrity and brain water transport balance. The upregulation of polymerase δ‐interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2‐mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss. Methods and Results Mouse BM model was induced by injecting mice with group B hemolytic streptococci via posterior cistern. Recombinant human Poldip2 (rh‐Poldip2) was administered intranasally at 1 hour after BM induction. Small interfering ribonucleic acid (siRNA) targeting Poldip2 was administered by intracerebroventricular (i.c.v) injection at 48 hours before BM induction. A specific inhibitor of matrix metalloproteinases (MMPs), UK383367, was administered intravenously at 0.5 hour before BM induction. Western blotting, immunofluorescence staining, quantitative real‐time PCR, neurobehavioral test, brain water content test, Evans blue (EB) permeability assay, transmission electron microscopy (TEM), and gelatin zymography were carried out. The results showed that Poldip2 was upregulated and AQP4 polarity was lost in mouse BM model. Both Poldip2 siRNA and UK383367 improved neurobehavioral outcomes, alleviated brain edema, preserved the integrity of BBB, and relieved the loss of AQP4 polarity in BM model. Rh‐Poldip2 upregulated the expression of MMPs and glial fibrillary acidic protein (GFAP) and downregulated the expression of β‐dystroglycan (β‐DG), zonula occludens‐1 (ZO‐1), occludin, and claudin‐5; whereas Poldip2 siRNA downregulated the expression of MMPs and GFAP, and upregulated β‐DG, ZO‐1, occludin, and claudin‐5. Similarly, UK383367 downregulated the expression of GFAP and upregulated the expression of β‐DG, ZO‐1, occludin, and claudin‐5. Conclusion Poldip2 inhibition alleviated brain edema and preserved the integrity of BBB partially by relieving the loss of AQP4 polarity via MMPs/β‐DG pathway.

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Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses

Cited by 43 publications

References 49 publications

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury

Poldip2 mediates blood‐brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model

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