Complexes of Amyloid-beta and Cystatin C in the Human Central Nervous System

A role for cystatin C (CysC) in the pathogenesis of Alzheimer's disease (AD) has been suggested by the genetic linkage of a CysC gene (CST3) polymorphism with late-onset AD, the co-localization of CysC with amyloid-beta (A beta) in AD brains, and binding of CysC to soluble A beta in vitro and in mouse models of AD. This study investigates the binding between A beta and CysC in the human central nervous system. While CysC binding to soluble A beta was observed in AD patients and controls, a SDS-resistant CysC/A beta complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. The association of CysC with A beta in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between A beta and CysC prevented A beta accumulation and fibrillogenesis in experimental systems, arguing that CysC plays a protective role in the pathogenesis of AD in humans and explains why decreases in CysC concentration caused by the CST3 polymorphism or by specific presenilin 2 mutations can lead to the development of the disease. Thus, enhancing CysC expression or modulating CysC binding to A beta have important disease-modifying effects, suggesting a novel therapeutic intervention for AD.