A mechanistic model to predict effects of cathepsin B and cystatin C on β-amyloid aggregation and degradation.

β-Amyloid (Aβ) aggregation is thought to initiate a cascade of neurodegenerative events in Alzheimer's disease (AD). Much effort is underway to develop strategies to reduce Aβ concentration or inhibit aggregation. Cathepsin B (CatB) proteolytically degrades Aβ into non-aggregating fragments but is potently inhibited by cystatin C (CysC).

Insights into the mechanism of cystatin C oligomer and amyloid formation and its interaction with β-amyloid.

Cystatin C (CysC) is a versatile and ubiquitously-expressed member of the cysteine protease inhibitor family that is present at notably high concentrations in cerebrospinal fluid. Under mildly denaturing conditions, CysC forms inactive domain-swapped dimers. A destabilizing mutation, L68Q, increases the rate of domain-swapping and causes a fatal amyloid disease, hereditary cystatin C amyloid angiopathy.

Expression, purification, and characterization of human cystatin C monomers and oligomers.

Human cystatin C (cysC) is a soluble basic protein belonging to the cysteine protease inhibitor family. CysC is a potent inhibitor of cathepsins--proteolytic enzymes that degrade intracellular and endocytosed proteins, remodel extracellular matrix, and trigger apoptosis. Inhibition is via tight reversible binding involving the N-terminus as well as two β-hairpin loops of cysC.