Abbreviations used: ABTS, 2,2′-azinobis(3-ethylbenzthiazoline-6-sulfonic acid; AD, Alzheimer’s disease; BSA, bovine serum albumin; DAB, 3,3′-diaminobenzidine; DFX, deferoxamine; DTPA, diethylene-triaminepentaacetic acid; HNE, 4-hydroxy-2-nonenal; MBTH, 3-methyl-2-benzothiazolinone hydrazone; MES, 2-(N-morpholino)ethanesulfonate; NFT, neurofibrillary tangles; SP, senile plaques.
In Situ Oxidative Catalysis by Neurofibrillary Tangles and Senile Plaques in Alzheimer’s Disease
A Central Role for Bound Transition Metals
Article first published online: 25 DEC 2001
Journal of Neurochemistry
Volume 74, Issue 1, pages 270–279, January 2000
How to Cite
Sayre, L. M., Perry, G., Harris, P. L. R., Liu, Y., Schubert, K. A. and Smith, M. A. (2000), In Situ Oxidative Catalysis by Neurofibrillary Tangles and Senile Plaques in Alzheimer’s Disease. Journal of Neurochemistry, 74: 270–279. doi: 10.1046/j.1471-4159.2000.0740270.x
- Issue published online: 25 DEC 2001
- Article first published online: 25 DEC 2001
- Alzheimer’s disease;
- Neurofibrillary tangles;
- Reactive oxygen species;
- Senile plaques
Abstract: There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer’s disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3′-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein τ, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.