Codeposition of Cystatin C with Amyloid-β Protein in the Brain of Alzheimer Disease Patients

Abstract

Immunohistochemical analysis of brains of patients with Alzheimer disease (AD) revealed that the cysteine proteinase inhibitor cystatin C colocalizes with amyloid beta-protein (Abeta) 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-Abeta and anti-cystatin C antibodies. Cystatin C immunoreactivity was also observed in amyloid deposits in the brain of transgenic mice overexpressing human beta 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 Abeta(x-42) showed intracellular immunoreactivity in the same neuronal subpopulation. It remains to be established whether the association of cystatin C to Abeta plays a primary role in amyloidogenesis of AD or is a late event in which the protein is bound to the previously formed Abeta amyloid fibrils.

Serum cystatin C and the risk of Alzheimer disease in elderly men

“…Cystatin C is an endogenous cysteine inhibitor, produced by nearly all human cells and available in all body fluids. 1 During the past decade, experimental, 2-7 genetic, [8][9][10] and clinical data 6,11,12 have suggested that cystatin C activity in the brain may protect against the development of Alzheimer disease (AD) by inhibition of A␤ aggregation, one of the pathologic hallmarks of AD. 13 Recently, it was shown that in a transgenic mouse model, cystatin C binds to soluble A␤, preventing its deposition in the brain.…”

Oligomerization and Transglutaminase Cross-linking of the Cystatin CRES in the Mouse Epididymal Lumen

“…Several cystatins have been shown to self-aggregate and form dimers and oligomers in vivo (13,14). Moreover, cystatin C forms part of the amyloid deposits in patients with cerebral amyloid angiopathy (15), including that associated with Alzheimer disease (16), whereas the L68Q variant form of cystatin C forms amyloid deposits in the cerebral blood vessels of patients who suffer from hereditary cystatin C amyloid angiopathy and who die from hemorrhagic stroke by the age of 30 (17). There is a growing body of evidence suggesting that the tendency to aggregate under certain environmental conditions may be a common trait of all cystatins rather than a characteristic of individual family members, and therefore it is feasible that CRES may also have the propensity to form amyloid (18).…”

Structure and Function of Stefin B Oligomers – Important Role in Amyloidogenesis

“…Human cystatin C is a risk factor for late onset Alzheimer's disease. The protein co-deposits with amyloid β peptide (Aβ peptide) amyloid plaques in patients with Alzheimer's disease [35]. Moreover, cystatin C binds to both the whole amyloid precursor protein (APP) and to Aβ peptide and it inhibits Aβ peptide amyloid fibril formation in vitro [36].…”