Bitan G, Tarus B, Vollers SS, Lashuel HA, Condron MM, Straub JE, Teplow DB.
A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization.
J Am Chem Soc. 2003 Dec 17;125(50):15359-65.
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There are many reasons for believing that Aβ peptides, in one form or another, are important factors in the pathogenesis of AD. Although some investigators are skeptical that these peptide are necessarily the most important factors leading to this disease, those who consider these peptides to be primary are concerned with two unresolved issues: (i) in what physical state do these peptides exert their neurotoxic effect ? and (ii) do these peptides act from within the neuron itself, or do they act on some component of the neuronal membrane by binding to its external surface?
A rich but confusing body of literature supports the idea that collections of Aβ peptides assemble into what are referred to as oligomeric states, and it is one or more of these forms that are believed to be toxic to neurons. There seems to be a general consensus that the larger amyloid fibrils, which by comparison to these "oligomers" are almost macroscopic in size, are more the consequence of neuronal degeneration that its cause. One problem with the oligomer hypothesis, at least up until the recent work by Bitan and Teplow, was the fact that the most convincing method for demonstrating their physical existence relied on their mobility on SDS gels. Since almost all protein aggregates are thought to be dissociated in SDS, with a few notable exceptions, it has always been unclear why Aβ oligomers resisted disaggregation, or, equally important, why such oligomers that were stable in SDS were necessarily in the same state under physiological conditions.
To answer this question definitively, for the first time in my opinion, Bitan and Teplow used a novel cross linking technique, referred to as PICUP, which, because it does not modify proteins before it links them together, was able to show that some but not all of the oligomeric states of Aβ that were previously demonstrated by SDS PAGE were not electrophoretic artifacts, but were indeed discrete aggregates of the specific peptides, and, most significantly, they demonstrated that the Aβ 2 peptide, long considered the most toxic of the two peptides, had a different oligomeric distribution than the Abeta 40 peptide. In this latest study they show that modifying methionine 35 of the Aβ 2 peptide has a striking effect on the oligomer distribution of Aβ 2, but does not change that of Aβ40. Aβ42 peptides that have Met 35 changed to either the sulfoxide or the sulfone show the same oligomeric distribution as Aβ40, implying , perhaps, that modification of Met 35 converts Aβ42 to the less toxic Aβ40 form.
These authors also report some preliminary attempts to explain the mechanisms of this conversion involving changes in redox state and hydrophobicity of the peptide that offer some interesting insights into how the oligomeric state of the Aβ42 peptide might be modified for therapeutic effect. It is suggested that oxidizing agents that specifically target Met35 of the Aβ42 peptide might have a beneficial effect. While this present study is not the first attempt to explore the effects of methionine oxidation on the behavior of Abeta peptide assembly, the experiments showing that the oxidation state of Met 35 differentially influences Aβ42 oligomer assembly are convincing, although the authors did not show that reducing Met 35 sulfoxide back to the native state reverses the effect. Finally one has to ask how these results bear on the question of how and where the Aβ peptides contribute to neuronal toxicity, assuming that they do. It is generally believed that these oligomers assemble outside neurons, somewhere in the extracellular compartment, but there is at the moment no way to tell whether they can also assemble inside cells. Many recent studies point to a role for an intracytoplasmic effect of the Aβ peptides in the early stages of the disease process, but no one has has yet figured out how to identify potentially toxic forms of Aβ that can act inside cells. The interesting speculations regarding the redox state of Met 35 provided in this paper might suggest some new approaches. VT Marchesi