Complexes of Amyloid-β and Cystatin C in the Human Central Nervous System (original) (raw)
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Cystatin C in Alzheimer's disease
Frontiers in Molecular Neuroscience, 2012
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.
Codeposition of Cystatin C with Amyloid-β Protein in the Brain of Alzheimer Disease Patients
Journal of Neuropathology and Experimental Neurology, 2001
Immunohistochemical analysis of brains of patients with Alzheimer disease (AD) revealed that the cysteine proteinase inhibitor cystatin C colocalizes with amyloid -protein (A) in parenchymal and vascular amyloid deposits. No evidence of cerebral hemorrhage was observed in any of the brains studied. Immunoelectron microscopy demonstrated dual staining of amyloid fibrils with anti-A and anti-cystatin C antibodies. Cystatin C immunoreactivity was also observed in amyloid deposits in the brain of transgenic mice overexpressing human  amyloid precursor protein. Massive deposition of the variant cystatin C in the cerebral vessels of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis is thought to be responsible for the pathological processes leading to stroke. Anti-cystatin C antibodies strongly labeled pyramidal neurons within cortical layers most prone to amyloid deposition in the brains of AD patients. Immunohistochemistry with antibodies against the carboxyl-terminus of A x-42 showed intracellular immunoreactivity in the same neuronal subpopulation. It remains to be established whether the association of cystatin C to A plays a primary role in amyloidogenesis of AD or is a late event in which the protein is bound to the previously formed A amyloid fibrils.
Cystatin C modulates cerebral β-amyloidosis
Nature Genetics, 2007
The CST3 Thr25 allele of CST3, which encodes cystatin C, leads to reduced cystatin C secretion and conveys susceptibility to Alzheimer's disease. Here we show that overexpression of human cystatin C in brains of APP-transgenic mice reduces cerebral amyloid-b deposition and that cystatin C binds amyloid-b and inhibits its fibril formation. Our results suggest that cystatin C concentrations modulate cerebral amyloidosis risk and provide an opportunity for genetic risk assessment and therapeutic interventions.
Cystatin C protects neuronal cells from amyloid-beta-induced toxicity
Journal of Alzheimer's disease : JAD, 2010
Multiple studies suggest that cystatin C (CysC) has a role in Alzheimer's disease (AD) and a decrease in CysC secretion is linked to the disease in patients with a polymorphism in the CysC gene. CysC binds amyloid-beta (Abeta) and inhibits formation of Abeta fibrils and oligomers both in vitro and in mouse models of amyloid deposition. Here we studied the effect of CysC on cultured primary hippocampal neurons and a neuronal cell line exposed to either oligomeric or fibrillar cytotoxic forms of Abeta. The extracellular addition of the secreted human CysC together with preformed either oligomeric or fibrillar Abeta increased cell survival. While CysC inhibits Abeta aggregation, it does not dissolve preformed Abeta fibrils or oligomers. Thus, CysC has multiple protective effects in AD, by preventing the formation of the toxic forms of Abeta and by direct protection of neuronal cells from Abeta toxicity. Therapeutic manipulation of CysC levels, resulting in slightly higher concentra...
Journal of Molecular Neuroscience, 2004
Cystatin C, an inhibitor of cysteine proteases, colocalizes with amyloid β (Aβ) in parenchymal and vascular amyloid deposits in brains of Alzheimer's disease (AD) patients, suggesting that cystatin C has a role in AD. Cystatin C also colocalizes with β amyloid precursor protein (βAPP) in transfected cultured cells. In vitro analysis of the association between the two proteins revealed that binding of cystatin C to full-length βAPP does not affect the level of Aβ secretion. Here we studied the effect of in vivo overexpression of cystatin C on the levels of endogenous brain Aβ. We have generated lines of transgenic mice expressing either wild-type human cystatin C or the Leu68Gln variant that forms amyloid deposits in the cerebral vessels of Icelandic patients with hereditary cerebral hemorrhage, under control sequences of the human cystatin C gene. Western blot analysis of brain homogenates was used to select lines of mice expressing various levels of the transgene. Analysis of Aβ40 and Aβ42 concentrations in the brain showed no difference between transgenic mice and their nontransgenic littermates. Thus, in vivo overexpression of human cystatin C does not affect Aβ levels in mice that do not deposit Aβ.
Cystatin C reduces the in vitro formation of soluble Aβ1‐42 oligomers and protofibrils
Scandinavian Journal of Clinical & Laboratory Investigation, 2007
There are an increasing number of genetic and neuropathological observations to suggest that cystatin C, an extracellular protein produced by all nucleated cells, might play a role in the pathophysiology of sporadic Alzheimer's disease (AD). Recent observations indicate that small and large soluble oligomers of the b-amyloid protein (Ab) impair synaptic plasticity and induce neurotoxicity in AD. The objective of the present study was to investigate the influence of cystatin C on the production of such oligomers in vitro. Co-incubation of cystatin C with monomeric Ab1-42 significantly attenuated the in vitro formation of Ab oligomers and protofibrils, as determined using electron microscopy (EM), dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, thioflavin T (ThT) spectrofluorimetry and gel chromatography. However, cystatin C did not dissolve preformed Ab oligomers. Direct binding of cystatin C to Ab was demonstrated with the formation of an initial 1:1 molar high-affinity complex. These observations suggest that cystatin C might be a regulating element in the transformation of monomeric Ab to larger and perhaps more toxic molecular species in vivo.
Cystatin C as a risk factor for Alzheimer disease
Neurology, 2005
Cystatin C, a protease inhibitor with widespread distribution, is upregulated in response to injury. Levels are elevated in the brains of patients with Alzheimer disease (AD). We compared frequencies for the CST 3 exon 1 polymorphism in patients with AD and controls. A proportional odds model indicated that the CST 3 A and APOE4 combination carried a high risk: a 14-fold elevation for men and 16-fold for women. These risks apply to risk at ages older than 64 years and to a shift in onset to ages younger than 65 years.
Alzheimer disease-associated cystatin C variant undergoes impaired secretion
Neurobiology of Disease, 2003
CST3 is the coding gene for cystatin C (CysC). CST3 B/B homozygosity is associated with an increased risk of developing Alzheimer disease. We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3. Pulse-chase experiments demonstrated that the release of the B variant of CysC has a different temporal pattern compared to that of the A one. Fibroblasts B/B homozygous displayed a reduced secretion of CysC due to a less efficient cleavage of the signal peptide, as suggested by high-resolution Western blot analysis and by in vitro assay. In the brain, the reduced level of CysC may represent the molecular factor responsible for the increased risk of Alzheimer disease.