Complexes of Amyloid-β and cystatin C in the human central nervous system

Weiqian Mi, Sonia S. Jung, Haung Yu, Stephen D. Schmidt, Ralph A. Nixon, Paul M. Mathews, Fabrizio Tagliavini, Efrat Levy

Research output: Contribution to journalArticlepeer-review

Abstract

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-β (Aβ) in AD brains, and binding of CysC to soluble Aβ in vitro and in mouse models of AD. This study investigates the binding between Aβ and CysC in the human central nervous system. While CysC binding to soluble Aβ was observed in AD patients and controls, a SDS-resistant CysC/Aβ complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. The association of CysC with Aβ in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between Aβ and CysC prevented Aβ 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 Aβ have important disease-modifying effects, suggesting a novel therapeutic intervention for AD.

Original languageEnglish
Pages (from-to)273-280
Number of pages8
JournalJournal of Alzheimer's Disease
Volume18
Issue number2
DOIs
Publication statusPublished - 2009

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Amyloid-β protein precursor
  • Cystatin C

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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