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.
However, the secreted variant cystatin C exhibited an increased susceptibility to a serine protease in conditioned media and in human cerebrospinal fluid, explaining its depletion from the cerebrospinal fluid of HCHWA-I patients.
We report a case of sporadic CAA with ICH in an elderly Croatian man with a mutation in cystatin C identical to that found in Icelandic hereditary cerebral hemorrhage with amyloidosis.
Based on the recent discovery of co-localization of beta/A4 and cystatin C in cortical blood vessels of patients with cerebral hemorrhages due to sporadic amyloid angiopathy and patients with Alzheimer's disease we investigated the presence of these two proteins in the cortical blood vessels of patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch (n = 11) and the Icelandic (n = 2) type.
To understand the molecular basis of the genetic defect, the gene encoding cystatin C was isolated from genomic DNA libraries made from normal tissue and the brain of an Icelandic patient with hereditary cerebral hemorrhage with amyloidosis (HCHWA-I).
This investigation demonstrates that hereditary cerebral hemorrhage with amyloidosis may be diagnosed by two laboratory methods: immunohistochemical investigation of cystatin C in brain tissue specimens and quantitation of cystatin C in cerebrospinal fluid.
Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases.
Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace.
These findings expand the number of APP mutations linked to hereditary cerebral hemorrhage with amyloidosis, reinforcing the link between this phenotype and codon 693 of APP.
To investigate amyloid accumulation by carbon 11-labeled Pittsburgh Compound B (11C-PiB) in hereditary cerebral amyloid angiopathy and APP locus duplication.
The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain.
A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D).
A beta-amyloid peptide variant related with familial Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis is poorly eliminated by cathepsin D.
Mutations within the beta-amyloid precursor protein (beta-APP) gene that cosegregate with early onset familial Alzheimer's disease (FAD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (HCHWA-D) have been reported.
The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCHWA-D.
Pericyte cultures with an ApoE epsilon 2/epsilon 3 genotype were more resistant to HCHWA-D A beta 1-40 treatment than cultures with a epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotype.
This study showed that the apolipoprotein E genotype does not modulate amyloid-related structural lesions in hereditary cerebral hemorrhage with amyloidosis of the Dutch type.
A beta-amyloid peptide variant related with familial Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis is poorly eliminated by cathepsin D.
Plaque-like lesions and amyloid angiopathy were investigated in the frontal cerebral cortex of four patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), using immunohistochemical [antibodies to beta amyloid protein (A beta), beta protein precursor (beta PP), synaptophysin, ubiquitin (UBQ), cathepsin D, paired helical filaments (PHF) and glial fibrillary acidic protein (GFAP)], enzymehistochemical (acid phosphatase) and silver [methenamine silver (MS) and Palmgren] staining methods.
We propose that calcification of CAA vessels in the observed HCHWA-D cases may be induced by extracellular OPN trapped in the fibrotic Col1 vessel wall, independently of the presence of vascular amyloid.