The mutant cystatin C protein forms aggregates and amyloid, within the central nervous system almost exclusively in connection with the vascular system.
These results indicate that up-regulation of Cst-3 in cortical neurons in layers 2-3 and 5 by Aβ oligomers may lead to increase in vulnerability of neurons.
Immunohistochemical studies have demonstrated the colocalization of the b-amyloid (A-beta) and cystatin C peptides within arteriolar walls in the AD brain.
Our results suggest that cystatin C concentrations modulate cerebral amyloidosis risk and provide an opportunity for genetic risk assessment and therapeutic interventions.
Other amyloid proteins involved in familial CAAs include 1) the mutant cystatin C (ACys) in hereditary cerebral hemorrhage with amyloidosis of Icelandic type, 2) variant transthyretins (ATTR) in meningo-vascular amyloidoses, 3) mutated gelsolin (AGel) in familial amyloidosis of Finnish type, 4) disease-associated prion protein (PrP(Sc)) in a variant of the Gerstmann-Sträussler-Scheinker syndrome, and 5) ABri and ADan in CAAs observed in the recently described BRI2 gene-related dementias, familial British dementia and familial Danish dementia, respectively.
The state of denaturation of L68Qcystatin C in vivo is thus a critical factor for the concentration of active cysteine proteinase inhibitor in cerebrospinal fluid and likely also for the development of amyloidosis, in HCCAA patients.
To study the cellular transport of L68Qcystatin C, the cystatin variant causing amyloidosis and brain haemorrhage in patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA).
Progressive dementia and leucoencephalopathy as the initial presentation of late onset hereditary cystatin-Camyloidosis. Clinicopathological presentation of two cases.
Increased body temperature accelerates aggregation of the Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy.
A variant of cystatin C lacking the first NH2-terminal residues and having one amino acid substitution at position 68 forms amyloid deposits mainly in the walls of brain arteries, causing fatal strokes in Icelandic patients with familial cerebral hemorrhage secondary to a form of an autosomal dominant amyloidosis.