Alzheimer's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Alzheimer's Disease, including details on diagnosis, memory loss, heredity, treatment, medication.

Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer's Abeta peptides.

Huang X, Atwood CS, Moir RD, Hartshorn MA, Tanzi RE, Bush AI

Department of Psychiatry, and Laboratory for Oxidation Biology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA. huangx@helix.mgh.harvard.edu

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 beta-amyloid (Abeta) deposition, accumulation, and incur neurotoxicity and synaptotoxicity in Alzheimer's disease (AD), and other amyloid-associated neurodegenerative diseases. However, Abeta is a high-affinity metalloprotein that aggregates in the presence of biometals (zinc, copper, and iron), and neocortical Abeta deposition is abolished by genetic ablation of synaptic zinc in transgenic mice. We now present in vitro evidence that trace (<or=0.8 microM) levels of zinc, copper, and iron, present as common contaminants of laboratory buffers and culture media, are the actual initiators of the classic Abeta1-42-mediated seeding process and Abeta oligomerization. Replicating the experimental conditions of earlier workers, we found that the in vitro precipitation and amyloidosis of Abeta1-40 (20 microM) initiated by Abeta1-42 (2 microM) were abolished by chelation of trace metal contaminants. Further, metal chelation attenuated formation of soluble Abeta 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 Abeta amyloidosis and oligomerization.

Published 3 December 2004 in J Biol Inorg Chem, 9(8): 954-60.
Full-text of this article is available online (may require subscription).

© 2004-2008 Alzheimer's Disease Research Today. All Rights Reserved.