期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 18, 期 2, 页码 273-280出版社
IOS PRESS
DOI: 10.3233/JAD-2009-1147
关键词
Alzheimer's disease; amyloid-beta; amyloid-beta protein precursor; cystatin C
资金
- National Institute of Neurological Disorders and Stroke [NS42029]
- National Institute on Aging [AG017617]
- American Heart Association [0040102N]
- Alzheimer's Association [IIRG-07-59699]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS042029] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG017617] Funding Source: NIH RePORTER
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.
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