Evidence that the β-Amyloid Plaques of Alzheimer's Disease Represent the Redox-silencing and Entombment of Aβ by Zinc

doi:10.1074/jbc.C000165200

Evidence that the β-Amyloid Plaques of Alzheimer's Disease Represent the Redox-silencing and Entombment of Aβ by Zinc*

From the ^‡Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the ^§Department of Psychiatry and Behavioral Science, University of Auckland School of Medicine, Auckland, New Zealand, the ^‖Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, and the ^**Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan

Abstract

Aβ binds Zn²⁺, Cu²⁺, and Fe³⁺ in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn²⁺ precipitates Aβ in vitro, and Cu²⁺ interaction with Aβ promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H₂O₂ (Aβ1–42 > Aβ1–40 > ratAβ1–40). Because Zn²⁺ is redox-inert, we studied the possibility that it may play an inhibitory role in H₂O₂-mediated Aβ toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu²⁺, Zn²⁺ rescued primary cortical and human embryonic kidney 293 cells that were exposed to Aβ1–42, correlating with the effect of Zn²⁺ in suppressing Cu²⁺-dependent H₂O₂formation from Aβ1–42. Since plaques contain exceptionally high concentrations of Zn²⁺, we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn²⁺in AD, where plaques form as the result of a more robust Zn²⁺ antioxidant response to the underlying oxidative attack.

Footnotes

↵* This work was supported by funds from the American Health Assistance Foundation, Prana Corp., Alzheimer's Association, by National Institute on Aging Grants R29-12686 and RO1-AG09287, and by the NH&MRC.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¶ Recipient of the New Zealand Neurological Foundation Miller Postgraduate Scholarship.
↵‡ To whom correspondence should be addressed: Director, Laboratory for Oxidation Biology, Massachusetts General Hospital, Bldg. 149, 13th St., Charlestown, MA 02129. Tel.: 617-726-8244; Fax: 617-724-9610; E-mail: bush@helix.mgh.harvard.edu.
Published, JBC Papers in Press, May 8, 2000, DOI 10.1074/jbc.C000165200
↵2 A. I. Bush and C. L. Masters, personal communication.
Abbreviations:

AD

Alzheimer's disease

8-OHG

8-OH guanosine

BSO

buthionine sulfoximine

DMEM

Dulbecco's minimum essential medium

TCEP

tris(2-carboxyethyl)phosphine hydrochloride

PBS

phosphate-buffered saline

MT

metallothionein
- Received March 15, 2000.
- Revision received April 27, 2000.
The American Society for Biochemistry and Molecular Biology, Inc.