Destructive Effects of Pyroptosis on Homeostasis of Neuron Survival Associated with the Dysfunctional BBB-Glymphatic System and Amyloid-Beta Accumulation after Cerebral Ischemia/Reperfusion in Rats
| Autor: | Qiang Zhang, Zhong-Hai Yu, Xiangting Li, Yaming Li, Yuanjin Chan, Zhongkuan Lyu, Dingfang Cai, Jun Xiang, Qiyue Li, Kaili Liu, Bing Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Agonist Programmed cell death Article Subject Cell Survival Amyloid beta medicine.drug_class Ischemia Neurosciences. Biological psychiatry. Neuropsychiatry Pharmacology Proinflammatory cytokine Rats Sprague-Dawley Pyroptosis medicine Animals Homeostasis Aquaporin 4 Neurons Amyloid beta-Peptides biology business.industry Brain medicine.disease Rats Neurology Blood-Brain Barrier Astrocytes Reperfusion Injury biology.protein Glymphatic system Microglia Neurology (clinical) business Glymphatic System RC321-571 Research Article |
| Zdroj: | Neural Plasticity Neural Plasticity, Vol 2021 (2021) |
| ISSN: | 1687-5443 2090-5904 |
| Popis: | Neuroinflammation-related amyloid-beta peptide (Aβ) accumulation after cerebral ischemia/reperfusion (I/R) accounts for cerebral I/R injuries and poststroke dementia. Recently, pyroptosis, a proinflammatory cell death, has been identified as a crucial pathological link of cerebral I/R injuries. However, whether pyroptosis acts as a trigger of Aβ accumulation after cerebral I/R has not yet been demonstrated. Blood-brain barrier (BBB) and glymphatic system mediated by aquaporin-4 (AQP-4) on astrocytic endfeet are important pathways for the clearance of Aβ in the brain, and pyroptosis especially occurring in astrocytes after cerebral I/R potentially damages BBB integrity and glymphatic function and thus influences Aβ clearance and brain homeostasis. In present study, the method of middle cerebral artery occlusion/reperfusion (MCAO/R) was used for building models of focal cerebral I/R injuries in rats. Then, we used lipopolysaccharide and glycine as the agonist and inhibitor of pyroptosis, respectively, Western blotting for detections of pyroptosis, AQP-4, and Aβ1-42 oligomers, laser confocal microscopy for observations of pyroptosis and Aβ locations, and immunohistochemical stainings of SMI 71 (a specific marker for BBB integrity)/AQP-4 and Nissl staining for evaluating, respectively, BBB-glymphatic system and neuronal damage. The results showed that pyroptosis obviously promoted the loss of BBB integrity and AQP-4 polarization, brain edema, Aβ accumulation, and the formation of Aβ1-42 oligomers and thus increased neuronal damage after cerebral I/R. However, glycine could inhibit cerebral I/R-induced pyroptosis by alleviating cytomembrane damage and downregulating expression levels of cleaved caspase-11/1, N-terminal gasdermin D, NLRP3 (nucleotide-binding domain, leucine-rich repeat containing protein 3), interleukin-6 (IL-6) and IL-1β and markedly abate above pathological changes. Our study revealed that pyroptosis is a considerable factor causing toxic Aβ accumulation, dysfunctional BBB-glymphatic system, and neurological deficits after cerebral I/R, suggesting that targeting pyroptosis is a potential strategy for the prevention of ischemic stroke sequelae including dementia. |
| Databáze: | OpenAIRE |
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