Cited by 1,009Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

Dramatic Aggregation of Alzheimer Aβ by Cu(II) Is Induced by Conditions Representing Physiological Acidosis

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Atwood, Craig S., Moir, Robert D., Huang, Xudong, Scarpa, Richard C., Bacarra, N. Michael E., Romano, Donna M., Hartshorn, Mariana A., Tanzi, Rudolph E. +1 more·1998·Journal of Biological Chemistry

Abstract

The cortical deposition of Abeta is an event that occurs in Alzheimer's disease, Down's syndrome, head injury, and normal aging. Previously, in appraising the effects of different neurochemical factors that impact upon the solubility of Abeta, we observed that Zn2+ was the predominant bioessential metal to induce the aggregation of soluble Abeta at pH 7.4 in vitro and that this reaction is totally reversible with chelation. We now report that unlike other biometals tested at maximal biological concentrations, marked Cu2+-induced aggregation of Abeta1-40 emerged as the solution pH was lowered from 7.4 to 6.8 and that the reaction was completely reversible with either chelation or alkalinization. This interaction was comparable to the pH-dependent effect of Cu2+ on insulin aggregation but was not seen for aprotinin or albumin. Abeta1-40 bound three to four Cu2+ ions when precipitated at pH 7.0. Rapid, pH-sensitive aggregation occurred at low nanomolar concentrations of both Abeta1-40 and Abeta1-42 with submicromolar concentrations of Cu2+. Unlike Abeta1-40, Abeta1-42 was precipitated by submicromolar Cu2+ concentrations at pH 7.4. Rat Abeta1-40 and histidine-modified human Abeta1-40 were not aggregated by Zn2+, Cu2+, or Fe3+, indicating that histidine residues are essential for metal-mediated Abeta assembly. These results indicate that H+-induced conformational changes unmask a metal-binding site on Abeta that mediates reversible assembly of the peptide. Since a mildly acidic e…

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Crossref · 10.1074/jbc.273.21.12817

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Authors
Atwood, C. S., Moir, R. D., Huang, X., Scarpa, R. C., Bacarra, N. M. E., Romano, D. M., Hartshorn, M. A., Tanzi, R. E., & Bush, A. I.
Affiliations
Harvard University (US)
Corresponding author
Bush, Ashley I.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1998-05
Volume
273
Issue
21
Pages
12817-12826
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2018333394
Cited by
1,009
References
97
Citations by year
2026: 13 · 2025: 15 · 2024: 12 · 2023: 16 · 2022: 14 · 2021: 22 · 2020: 26 · 2019: 28 · 2018: 26 · 2017: 33 · 2016: 24 · 2015: 40 · 2014: 38 · 2013: 39 · 2012: 59
FWCI
20.04
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (1R29AG1268601)
  • National Cancer Institute
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
amyloid-beta aggregation, copper(II), acidosis, pH-dependent aggregation, Alzheimer's disease, Aβ40, amyloid-beta 42, zinc, histidine residues, metal ion binding, amyloid plaques, metal chelation, inflammation, neurodegeneration
MeSH terms
Acidosis, Alzheimer Disease, Animals, Copper, Humans, Hydrogen-Ion Concentration, Peptide Fragments, Protein Binding, Zinc, Amyloid beta-Peptides, Rats

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