Changes in Distribution of Cystatin C, Apolipoprotein E and Ferritin in Rat Hypothalamus after Hypophysectomy

Katakai, Kenji; Shinoda, Motoo; Kabeya, Kenji; Watanabe, Masashi; Ohe, Yoshihide; Mori, Masatomo; Ishikawa, Koichi

doi:10.1046/j.1365-2826.1997.t01-1-00566.x

Cited by 19 publications

(12 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alzheimer’s disease is characterized by abnormal accumulation of certain brain proteins, including β-amyloid and tau [83]. Cathepsin B functions as a β-secretase in the production of β-amyloid peptides [84], and human cystatins B and C have the ability to directly bind to β-amyloid peptides [85], [86], [87], [88]. Skerget and coworkers found that cystatin B prevents β-amyloid fibril formation in vitro [89].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Macrophage-Secreted Cathepsin B Contributes to HIV-1-Linked Neuronal Apoptosis

et al. 2012

View full text Add to dashboard Cite

Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1ADA infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages.

show abstract

Section: Discussionmentioning

confidence: 99%

Dysregulation of Macrophage-Secreted Cathepsin B Contributes to HIV-1-Linked Neuronal Apoptosis

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Changes in the levels of CysC in the CSF and brain in various neurodegenerative diseases suggest important roles for the secreted protein in these disorders. In support of such a role, CysC level dysregulation was also observed in animal models of neurodegenerative conditions caused by facial nerve axotomy (Miyake et al, 1996), noxious input to the sensory spinal cord (Yang et al, 2001), perforant path transections (Ying et al, 2002), hypophysectomy (Katakai et al, 1997), transient forebrain ischemia (Palm et al, 1995; Ishimaru et al, 1996), photothrombotic stroke (Pirttila and Pitkanen, 2006), and induction of epilepsy (Aronica et al, 2001; Hendriksen et al, 2001; Lukasiuk et al, 2002). Augmented CysC expression in the neurodegenerative states puts forward two conflicting theories whether enhanced CysC expression is causing or further exacerbating already initiated neurodegenerative changes or, alternatively, it is an endogenous neuroprotective response to the disease (reviewed in Gauthier et al, 2011).…”

Section: Introductionmentioning

confidence: 92%

Cystatin C in Alzheimer's disease

Kaur¹,

Levy²

2012

Front. Mol. Neurosci.

109

View full text Add to dashboard Cite

Changes in expression and secretion levels of cystatin C (CysC) in the brain in various neurological disorders and in animal models of neurodegeneration underscore a role for CysC in these conditions. A polymorphism in the CysC gene (CST3) is linked to increased risk for Alzheimer's disease (AD). AD pathology is characterized by deposition of oligomeric and fibrillar forms of amyloid β (Aβ) in the neuropil and cerebral vessel walls, neurofibrillary tangles composed mainly of hyperphosphorylated tau, and neurodegeneration. The implication of CysC in AD was initially suggested by its co-localization with Aβ in amyloid-laden vascular walls, and in senile plaque cores of amyloid in the brains of patients with AD, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), and cerebral infarction. CysC also co-localizes with Aβ amyloid deposits in the brains of non-demented aged individuals. Multiple lines of research show that CysC plays protective roles in AD. In vitro studies have shown that CysC binds Aβ and inhibits Aβ oligomerization and fibril formation. In vivo results from the brains and plasma of Aβ-depositing transgenic mice confirmed the association of CysC with the soluble, non-pathological form of Aβ and the inhibition of Aβ plaques formation. The association of CysC with Aβ was also found in brain and in cerebrospinal fluid (CSF) from AD patients and non-demented control individuals. Moreover, in vitro results showed that CysC protects neuronal cells from a variety of insults that may cause cell death, including cell death induced by oligomeric and fibrillar Aβ. These data suggest that the reduced levels of CysC manifested in AD contribute to increased neuronal vulnerability and impaired neuronal ability to prevent neurodegeneration. This review elaborates on the neuroprotective roles of CysC in AD and the clinical relevance of this protein as a therapeutic agent.

show abstract

“…That CSF CysC levels are altered during ALS disease progression is consistent with the localization of CysC to Bunina bodies, small intraneuronal inclusions contained in degenerating motor neurons that are a specific neuropathologic feature of ALS (Okamoto et al, 2008). Changes in brain CysC levels have also been observed in diverse animal models of neurodegenerative conditions including those caused by facial nerve axotomy (Miyake et al, 1996), noxious input to the sensory spinal cord (Yang et al, 2001), perforant path transections (Ying et al, 2002), hypophysectomy (Katakai et al, 1997), transient forebrain ischemia (Ishimaru et al, 1996; Palm et al, 1995), photothrombotic stroke (Pirttila and Pitkanen, 2006), and induction of epilepsy (Aronica et al, 2001; Hendriksen et al, 2001; Lukasiuk et al, 2002). While these findings argue that CysC levels in the CSF and the brain are broadly responsive to brain injury, CysC appears to also be a sensitive marker of ongoing neuronal injury and one that shows progressive disruption during disease pathology (Gauthier et al, 2011; Wilson et al).…”

Section: Cysc In Diseasementioning

confidence: 99%

Cystatin C in aging and in Alzheimer’s disease

Mathews

Levy

2016

Ageing Research Reviews

View full text Add to dashboard Cite

Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.

show abstract

Changes in Distribution of Cystatin C, Apolipoprotein E and Ferritin in Rat Hypothalamus after Hypophysectomy

Cited by 19 publications

References 7 publications

Dysregulation of Macrophage-Secreted Cathepsin B Contributes to HIV-1-Linked Neuronal Apoptosis

Dysregulation of Macrophage-Secreted Cathepsin B Contributes to HIV-1-Linked Neuronal Apoptosis

Cystatin C in Alzheimer's disease

Cystatin C in aging and in Alzheimer’s disease

Contact Info

Product

Resources

About