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

Issue title: Mini-Forum: Roles of Amyloid-β and Tau Phosphorylation in Neuronal Repair and Protection

Guest editors: Garth Bissette

Article type: Research Article

Authors: Mi, Weiqian^a | Jung, Sonia S.^{a; f} | Yu, Haung^{a; b; g} | Schmidt, Stephen D.^a | Nixon, Ralph A.^{a; b; d} | Mathews, Paul M.^{a; b} | Tagliavini, Fabrizio^e | Levy, Efrat^{a; b; c; *}

Affiliations: [a] Nathan S. Kline Institute, Orangeburg, New York, USA | [b] Department of Psychiatry, New York University School of Medicine, New York, NY, USA | [c] Department of Pharmacology, New York University School of Medicine, New York, NY, USA | [d] Departments of Cell Biology, New York University School of Medicine, New York, NY, USA | [e] “Carlo Besta”, National Neurological Institute, Milan 20133, Italy | [f] Present address: Centocor R&D Inc., Radnor, PA, USA | [g] Present address: Taub Institute, Columbia University, New York, NY, USA | Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence: [*] Corresponding author: Efrat Levy, Nathan S. Kline Institute, Orangeburg, NY 10962, USA. Tel.: +1 845 398 5540; Fax: +1 845 398 5422; E-mail: elevy@nki.rfmh.org.

Note: [] Communicated by Luciano D’Adamio

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.

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cystatin C

DOI: 10.3233/JAD-2009-1147

Journal: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 273-280, 2009