Like good cholesterol and bad cholesterol, the Alzheimer's community has realized that there may also be good Aβ and bad Aβ. What if an antibody was developed to target only the latter? A tall order, yet scientists from the University of California, Irvine, may have done just that. Reporting in yesterday’s Science, Charles Glabe and colleagues describe a remarkable antibody that only recognizes and binds to soluble oligomers of Aβ. This is significant because not only are these oligomers the building blocks of fibrillar Aβ, but they are also more neurotoxic (see ARF related news story).
First author Rakez Kayed and coworkers raised the antibody by vaccinating rabbits with synthetic molecules designed to mimic the structure of soluble Aβ oligomers. When the authors tested the antibody, they found it reacted with the oligomers but failed to recognize soluble monomers or insoluble fibrillar forms of the peptide. In an astonishing twist, Kayed found that the antibody also recognized soluble oligomers of other amyloid proteins, including α-synuclein, human insulin, islet amyloid polypeptide (IAPP), and prion peptide 106-126. This suggests that oligomers of all these unrelated proteins must have a common structural surface based on their peptide bond backbone and quite irrespective of their particular amino acid side chains.
Kayed and colleagues next asked if the antibody could prevent the toxic effects of amyloid on cultured neurons. When the latter were incubated with soluble oligomers of Aβ40 or Aβ42, only about 20 percent of cells remained viable, yet including the oligomer antibody in the cell culture increased this number to 80 percent. The antibody was similarly able to rescue cells from the toxic effects of other soluble oligomers, including insulin, IAPP, lysozyme, and polyQ proteins. One implication is that one antibody might be useful against a variety of amyloid disorders.
In AD brain samples, the antibody stained clusters of Aβ deposits distinct from those fibrillar deposits detected by thioflavin-S. Furthermore, the antibody failed to detect any deposits in samples from dementia-free individuals, despite the presence of occasional Aβ plaques in these people’s brains. The antibody also reacts with brain lysates from people who have exhibited early signs of AD. Together, this leads the authors to suggest that soluble Aβ oligomers, also called Aβ-derived diffusible ligands (ADDLs), "may represent the initial stage of amyloid deposition."—Tom Fagan
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- Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003 Apr 18;300(5618):486-9. PubMed.