Cystatin C Is a Crucial Endogenous Protective Determinant Against Stroke

Fang, Zongping; Deng, Jiao; Wu, Zhixin; Dong, Beibei; Wang, Shiquan; Chen, Xiaodan; Nie, Hongguang; Dong, Hailong; Xiong, Lize

doi:10.1161/strokeaha.116.014975

Cited by 32 publications

(34 citation statements)

References 26 publications

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“…A recent study demonstrated that CysC prevents oxidative injury [10]. Exogenous CysC is neuroprotective by reducing the infarct volume in ischemic stroke in rats [13]; this phenomenon is in agreement with our recent result [7]. However, besides the maintenance of lysosomal integrity [7], little is known about the mechanism of elevated CysC in mediating the neuroprotection induced by HBO preconditioning.…”

Section: Discussionsupporting

confidence: 90%

“…We have shown that the level of CysC is significantly increased after HBO preconditioning in non-ischemic brain [7]. To explore the role of CysC after ischemic injury, we first examined its expression at different time points after cerebral I/R.…”

Section: Resultsmentioning

confidence: 99%

“…A genome editing technique based on transcriptional activator-like effector nucleases (TALEN) was used to produce CysC-knockout rats by targeting exon 1 of CysC [7]. To confirm the efficiency of CysC deletion, sequencing analysis was performed to detect base-pair deletions and western blot to assess the protein levels of CysC.…”

Section: Methodsmentioning

confidence: 99%

“…3-Methyladenine (3-MA) (30 μg in 10 μL artificial cerebrospinal fluid, Sigma-Aldrich) was administered by intracerebroventricular injection 30 min before ischemia [8], while exogenous CysC (40 μg/kg) dissolved in artificial cerebrospinal fluid was delivered into the right lateral ventricle 30 min after reperfusion [7]. …”

Section: Methodsmentioning

confidence: 99%

“…Although neuroprotection is well defined, the mechanisms underlying HBO preconditioning remain elusive. Recently, we reported that Cystatin C (CysC), a lysosomal cysteine protease inhibitor, is a key mediator of the neuroprotection induced by HBO preconditioning [7]. However, how CysC changes after stroke and the mechanism underlying the neuroprotection mediated by CysC are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C

et al. 2018

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We have previously reported that Cystatin C (CysC) is a pivotal mediator in the neuroprotection induced by hyperbaric oxygen (HBO) preconditioning; however, the underlying mechanism and how CysC changes after stroke are not clear. In the present study, we demonstrated that CysC expression was elevated as early as 3 h after reperfusion, and this was further enhanced by HBO preconditioning. Concurrently, LC3-II and Beclin-1, two positive-markers for autophagy induction, exhibited increases similar to CysC, while knockdown of CysC blocked these elevations. As a marker of autophagy inhibition, p62 was downregulated by HBO preconditioning and this was blocked by CysC knockdown. Besides, the beneficial effects of preserving lysosomal membrane integrity and enhancing autolysosome formation induced by HBO preconditioning were abolished in CysC−/− rats. Furthermore, we demonstrated that exogenous CysC reduced the neurological deficits and infarct volume after brain ischemic injury, while 3-methyladenine partially reversed this neuroprotection. In the present study, we showed that CysC is biochemically and morphologically essential for promoting autophagic flux, and highlighted the translational potential of HBO preconditioning and CysC for stroke treatment.Electronic supplementary materialThe online version of this article (10.1007/s12264-018-0313-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C

et al. 2018

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Association between serum cystatin C level and post‐stroke cognitive impairment in patients with acute mild ischemic stroke

Chen

Xiu-li

2022

Brain and Behavior

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Background: Mild ischemic stroke (MIS) has been proved to be closely related to poststroke cognitive impairment (PSCI). However, there are relatively few studies on the risk factors of MIS. We aimed to evaluate the relationship between serum cystatin C (CysC) level and cognitive function in patients with acute MIS. Methods: Four hundred consecutive patients with acute MIS were screened and 281 patients were eligible for this study. The serum CysC levels were detected within 24 h after admission. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at 3 months after acute MIS. Logistic regression was used to identify the predictors of PSCI, and the receiver operating characteristic (ROC) curve was applied to explore the optimal cut-off value.Results: One hundred sixty-four (58.4%) patients were diagnosed with PSCI at 3 months follow-up. The serum CysC levels in patients with PSCI were significantly higher than patients without PSCI (p < .001). The binary logistic regression analysis showed that higher serum CysC level was an independent predictor for PSCI at 3 months (odds ratio [OR], 5.745; 95% confidence interval, [CI], 1.089-30.311; p = 0.039). The ROC curve showed that area under the curve (AUC) was 0.723, and at a 0.945 mg/l CysC cut-off point, the sensitivity and specificity for PSCI at 3 months were 79.9% and 58.1%, respectively. Conclusion:Our findings suggested that the serum CysC levels were increased after acute MIS, and higher serum CysC levels at baseline might be an independent risk factor for PSCI in patients with acute MIS, but further research are warranted.

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Cystatin C loaded in brain-derived extracellular vesicles rescues synapses after ischemic insult in vitro and in vivo

Gui,

Kim,

Brenna

et al. 2024

Cell. Mol. Life Sci.

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Synaptic loss is an early event in the penumbra area after an ischemic stroke. Promoting synaptic preservation in this area would likely improve functional neurological recovery. We aimed to detect proteins involved in endogenous protection mechanisms of synapses in the penumbra after stroke and to analyse potential beneficial effects of these candidates for a prospective stroke treatment. For this, we performed Liquid Chromatography coupled to Mass Spectrometry (LC–MS)-based proteomics of synaptosomes isolated from the ipsilateral hemispheres of mice subjected to experimental stroke at different time points (24 h, 4 and 7 days) and compared them to sham-operated mice. Proteomic analyses indicated that, among the differentially expressed proteins between the two groups, cystatin C (CysC) was significantly increased at 24 h and 4 days following stroke, before returning to steady-state levels at 7 days, thus indicating a potential transient and intrinsic rescue mechanism attempt of neurons. When CysC was applied to primary neuronal cultures subjected to an in vitro model of ischemic damage, this treatment significantly improved the preservation of synaptic structures. Notably, similar effects were observed when CysC was loaded into brain-derived extracellular vesicles (BDEVs). Finally, when CysC contained in BDEVs was administered intracerebroventricularly to stroked mice, it significantly increased the expression of synaptic markers such as SNAP25, Homer-1, and NCAM in the penumbra area compared to the group supplied with empty BDEVs. Thus, we show that CysC-loaded BDEVs promote synaptic protection after ischemic damage in vitro and in vivo, opening the possibility of a therapeutic use in stroke patients.

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Cystatin C Is a Crucial Endogenous Protective Determinant Against Stroke

Abstract: CysC is a crucial determinant contributing to endogenous neuroprotection. It is also a novel candidate for stroke treatment through maintaining lysosomal membrane integrity.

Cited by 32 publications

References 26 publications

Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C

Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C

Association between serum cystatin C level and post‐stroke cognitive impairment in patients with acute mild ischemic stroke

Cystatin C loaded in brain-derived extracellular vesicles rescues synapses after ischemic insult in vitro and in vivo

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