Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B

Nagai, Atsushi; Ryu, Jae K.; Terashima, Masaharu; Tanigawa, Yoshinobu; Wakabayashi, Kiryo; McLarnon, James G.; Kobayashi, Shotai; Masuda, Junichi; Kim, Seung Up

doi:10.1016/j.brainres.2005.10.063

Cited by 53 publications

(39 citation statements)

References 39 publications

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“…The use of cathepsin-B inhibitors has also proved therapeutically relevant in models of ischemia and trauma, reducing lesion size, and improving outcomes after injury (Yoshida et al, 2002). Other studies, however, determined that cathepsin-B has a pro-survival function that counteracts cathepsin-D signaling (Nagai et al, 2005). These conflicting roles show the complexity of cathepsin-B signaling and will require further investigation to determine the exact role of the redistribution seen in membrane porated neurons.…”

Section: Discussionmentioning

confidence: 99%

Increased Intracranial Pressure after Diffuse Traumatic Brain Injury Exacerbates Neuronal Somatic Membrane Poration but not Axonal Injury: Evidence for Primary Intracranial Pressure-Induced Neuronal Perturbation

Lafrenaye

McGinn

Povlishock

2012

J Cereb Blood Flow Metab

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Increased intracranial pressure (ICP) associated with traumatic brain injury (TBI) is linked to increased morbidity. Although our understanding of the pathobiology of TBI has expanded, questions remain regarding the specific neuronal somatic and axonal damaging consequences of elevated ICP, independent of its impact on cerebral perfusion pressure (CPP). To investigate this, Fischer rats were subjected to moderate TBI. Measurements of ICP revealed two distinct responses to injury. One population exhibited transient increases in ICP that returned to baseline levels acutely, while the other displayed persistent ICP elevation (>20 mm Hg). Utilizing these populations, the effect of elevated ICP on neuronal pathology associated with diffuse TBI was analyzed at 6 hours after TBI. No difference in axonal injury was observed, however, rats exhibiting persistently elevated ICP postinjury revealed a doubling of neurons with chronic membrane poration compared with rats exhibiting only transient increases in ICP. Elevated postinjury ICP was not associated with a concurrent increase in DNA damage; however, traditional histological assessments did reveal increased neuronal damage, potentially associated with redistribution of cathepsin-B from the lysosomal compartment into the cytosol. These findings indicate that persistently increased ICP, without deleterious alteration of CPP, exacerbates neuronal plasmalemmal perturbation that could precipitate persistent neuronal impairment and ultimate neuronal death.

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Section: Discussionmentioning

confidence: 99%

Increased Intracranial Pressure after Diffuse Traumatic Brain Injury Exacerbates Neuronal Somatic Membrane Poration but not Axonal Injury: Evidence for Primary Intracranial Pressure-Induced Neuronal Perturbation

Lafrenaye

McGinn

Povlishock

2012

J Cereb Blood Flow Metab

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“…59 The aforementioned association with cystatin C might also support the idea of a direct neural toxic effect. 60 Yet it is important to note that the pathways linking CKD and dementia are not mutually exclusive but might work additively or even synergistically. Clearly, more studies into plausible underlying pathways are needed.…”

Section: Continuedmentioning

confidence: 99%

Dementia risk in renal dysfunction

et al. 2017

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Objective: Renal dysfunction has been linked with increased risk for cognitive impairment and dementia, but studies are conflicting. For that reason, the aim of the present systematic review and meta-analysis is to summarize the best available evidence on the prospective association between potential markers of renal dysfunction and development of cognitive impairment or dementia.Methods: Medline, Embase, and Cochrane Database of Systematic Reviews were searched for potential publications until August 1, 2016. Studies were eligible if they fulfilled the following criteria: population-based study, prospective design, $100 participants, aged $45 years, $1 year follow-up, and cognition/dementia outcomes. Where appropriate, random effects meta-analyses were conducted yielding pooled odds ratios (OR) and 95% confidence intervals (CI).Results: Twenty-two out of 8,494 abstracts fulfilled the eligibility criteria. Sufficient evidence was found for albuminuria, mixed results for estimated glomerular filtration rate (eGFR), insufficient support for cystatin C, and tentative evidence for serum creatinine and creatinine clearance. Meta-analyses of 5 studies representing 27,805 persons showed a 35% increased risk of cognitive impairment or dementia in those with albuminuria (OR 1.35, 95% CI 1.06-1.73, p 5 0.015), whereas eGFR ,60 mL/min/1.73 m 2 showed no significant association (OR 1.28, 95% CI 0.99-1.65, p 5 0.063). No meta-analyses could be done for serum creatinine, creatinine clearance, or cystatin C. Conclusions:The overall evidence for an association between renal dysfunction and cognitive impairment or dementia is modest. Evidence suggests that albuminuria is associated with higher odds of developing cognitive impairment or dementia. Renal dysfunction has been considered a candidate risk factor for cognitive impairment and dementia.1-3 The kidneys and the brain, both being end organs, are susceptible to vascular damage due to broadly similar anatomic and hemodynamic features. 4 Chronic kidney disease (CKD) and dementia share a similar risk factor profile including hypertension, diabetes mellitus, or hyperlipidemia, and in both conditions a high prevalence of small vessel disease, silent brain infarcts, white matter pathology, and microbleeds was reported.2,3,5-8 Hence, several pathways may underlie the association between CKD and cognitive impairment, including shared vascular factors or a direct neurotoxic effect of uremia. 2,9 Worldwide, the number of people with dementia has increased.

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“…88 In contrast, endogenous cystatin C inhibitor overexpression induced neuronal cell death associated with caspase-3 activation in vivo and in vitro. 89 Furthermore, Yu et al 90 reported that cystatin C-deficient mice exhibited increased cathepsin L expression and activity and reduced epithelial apoptosis. The antiapoptotic molecules Bcl-2, Bcl-xL, Mcl-1, and XLAP (X-chromosomelinked inhibitor of apoptosis) are targeted by the lysosomal cathepsins B and L in several human cancer cell lines.…”

Section: Cathepsins In Cardiomyopathymentioning

confidence: 99%