Legumain knockout improved cognitive impairment via reducing neuroinflammation in right unilateral common carotid artery occlusion mice

Life Sci. 2021 Nov 15;285:119944. doi: 10.1016/j.lfs.2021.119944. Epub 2021 Sep 10.

Abstract

Aims: Chronic cerebral hypoperfusion (CCH) is a state of chronic cerebral blood flow reduction, and it is the main cause of cognitive impairment and neurodegenerative diseases. The abnormal upregulation of legumain, a lysosomal cysteine protease, trigger synaptic plasticity impairment and neuroinflammation, which are involved in the underlying pathophysiology of CCH. At present, few studies have reported the role of legumain in cognitive impairment caused by CCH. In our study, we aimed to investigate the involvement of legumain knockout in cognitive function and neuroinflammation in a CCH mouse model.

Main methods: In this study, right unilateral common carotid artery occlusion (rUCCAO) was used to simulate the pathological state of cerebral ischemic injury. Various behavioural tests were executed to assess cognitive performance. In vivo electrophysiological recordings were used to measure synaptic functions. Western blotting, Golgi staining, haematoxylin/eosin staining, and immunofluorescence assays were conducted to examine pathological changes and molecular mechanisms.

Key findings: The data showed that the level of legumain was significantly increased in the hippocampus of mice subjected to rUCCAO. Legumain knockout significantly improved cognitive function and synaptic plasticity induced by rUCCAO, suggesting that legumain knockout-regulation effectively protected against CCH-induced behavioural dysfunctions. Moreover, legumain knockout suppressed rUCCAO-induced microglial activation, reduced the abnormal expression of inflammatory cytokines and the inflammasome complex, and impeded the activation of P65 and pyroptosis.

Significance: These findings suggest that legumain is an effective regulator of CCH, and may be an ideal target for the development of cerebral ischemia treatments in the future.

Keywords: Cognitive function; Hypoperfusion; Legumain; Neuroinflammation; Synaptic plasticity; hippocampus.

MeSH terms

  • Animals
  • Brain Ischemia / enzymology
  • Brain Ischemia / etiology*
  • Brain Ischemia / pathology
  • Carotid Stenosis / complications*
  • Carotid Stenosis / enzymology*
  • Carotid Stenosis / genetics
  • Cerebrovascular Circulation / genetics*
  • Cognitive Dysfunction / enzymology
  • Cognitive Dysfunction / etiology*
  • Cognitive Dysfunction / pathology
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / physiology*
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Hippocampus / enzymology
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / physiology
  • Neuronal Plasticity / genetics
  • Pyroptosis / genetics
  • Transcription Factor RelA / metabolism

Substances

  • Rela protein, mouse
  • Transcription Factor RelA
  • Cysteine Endopeptidases
  • asparaginylendopeptidase