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.

Abstract

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 Aβ 1-42 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 Aβ 1-42 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.

• Authors: Zhongkuan Lyu, Yuanjin Chan, Qiyue Li, Qiang Zhang, Kaili Liu, Jun Xiang, Xiangting Li, Dingfang Cai, Yaming Li, Bing Wang, Zhonghai Yu
• Journal: Neural plasticity (Neural Plast) Vol. 2021 Pg. 4504363 ( 2021) ISSN: 1687-5443 [Electronic] United States
• PMID: 34434229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Zhongkuan Lyu et al.

Chemical References

• Amyloid beta-Peptides
• Aquaporin 4

Topics

• Amyloid beta-Peptides (metabolism)
• Animals
• Aquaporin 4 (metabolism)
• Astrocytes (metabolism, pathology)
• Blood-Brain Barrier (metabolism, pathology)
• Brain (metabolism, pathology)
• Cell Survival (physiology)
• Glymphatic System (pathology, physiology)
• Homeostasis (physiology)
• Male
• Microglia (metabolism, pathology)
• Neurons (metabolism, pathology)
• Pyroptosis (physiology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism, pathology)