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- Title
Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer’s Aβ peptides.
- Authors
Xudong Huang; Atwood, Craig S.; Moir, Robert D.; Hartshorn, Mariana A.; Tanzi, Rudolph E.; Bush, Ashley I.
- Abstract
Nucleation-dependent protein aggregation (“seeding”) and amyloid fibril-free formation of soluble SDS-resistant oligomers (“oligomerization”) by hydrophobic interaction is an in vitro model thought to propagate β-amyloid (Aβ) deposition, accumulation, and incur neurotoxicity and synaptotoxicity in Alzheimer’s disease (AD), and other amyloid-associated neurodegenerative diseases. However, Aβ is a high-affinity metalloprotein that aggregates in the presence of biometals (zinc, copper, and iron), and neocortical Aβ deposition is abolished by genetic ablation of synaptic zinc in transgenic mice. We now present in vitro evidence that trace (≤0.8 µM) levels of zinc, copper, and iron, present as common contaminants of laboratory buffers and culture media, are the actual initiators of the classic Aβ1–42-mediated seeding process and Aβ oligomerization. Replicating the experimental conditions of earlier workers, we found that the in vitro precipitation and amyloidosis of Aβ1–40 (20 µM) initiated by Aβ1–42 (2 µM) were abolished by chelation of trace metal contaminants. Further, metal chelation attenuated formation of soluble Aβ oligomers from a cell-free culture medium. These data suggest that protein self-assembly and oligomerization are not spontaneous in this system as previously thought, and that there may be an obligatory role for metal ions in initiating Aβ amyloidosis and oligomerization.
- Publication
Journal of Biological Inorganic Chemistry (JBIC), 2004, Vol 9, Issue 8, p954
- ISSN
0949-8257
- Publication type
Academic Journal
- DOI
10.1007/s00775-004-0602-8