SOPHIE WILKINSON

Dobson

Selkoe

Aggregates of misfolded proteins are characteristic of degenerative neurological disorders such as Alzheimer's disease. But do these amyloid fibrils or plaques cause the diseases? Evidence is accumulating that the plaques may be less harmful than the smaller intermediates that combine to form them.

Plaques that develop in the brains of Alzheimer's patients are built up from fibrils composed of hundreds or more amyloid- peptide (A) molecules. Now, Dennis J. Selkoe and Dominic M. Walsh of Harvard Medical School's neurology department; Michael J. Rowan and Igor Klyubin of the pharmacology and therapeutics department at Trinity College, Dublin; and colleagues have demonstrated that oligomers composed of just a few Ab molecules--rather than the larger fibrils or individual Ab monomers--may be the most dangerous entities for brain cells [Nature, 416, 535 (2002)].

The Selkoe team, which is the first to examine the effect of defined oligomers in vivo, injected human A monomers and oligomers into the brains of anesthetized rats. They determined that the oligomers "markedly inhibited hippocampal long-term potentiation (LTP)," whereas the monomers had no effect. LTP is a measure of learning and memory function, capabilities that are degraded in Alzheimer's patients.

"This is the first study that connects in vivo synaptotoxicity with a chemically defined form of natural A," Selkoe tells C&EN. "It puts the smoking gun in the hands of the oligomers. And this fits in with a broad theme that's emerging from studies of Parkinson's, Huntington's, and other neurodegenerative diseases." He adds that fibrils may still participate in the progression of the disease, probably as a reservoir of oligomers.

MISCUE Polypeptide chains can form normal proteins or misfolded proteins that cluster together, ultimately forming fibrils consisting of hundreds of chains.

The Harvard/Trinity team also determined that the g-secretase inhibitors known as DAPM and MWIII-20 offer a prototype approach for treating protein-folding disorders.

The work of Selkoe and his colleagues is given added weight by another report on protein aggregates in the same issue of Nature. Massimo Stefani, professor of biochemistry at the University of Florence, and Christopher M. Dobson, professor of chemical and structural biology at the University of Cambridge, and their coworkers examined intermediates that formed as misfolded protein monomers coalesced into full-blown aggregates [416, 507 (2002)]. Although the researchers were working with proteins that don't cause disease, they found that the "species formed early in the aggregation of these non-disease-associated proteins are highly cytotoxic." Their fully formed fibrils, on the other hand, are not.

Dobson believes the intermediates are "pretty disorganized, with all sorts of 'sticky' hydrophobic amino acid residues exposed on their surfaces." That contrasts with properly folded proteins that tuck these groups in their interior. "Unlike the normal forms of proteins, therefore, these intermediates can probably bind rather indiscriminately to cells and their components" with detrimental results.

In a commentary accompanying the articles, R. John Ellis and Teresa J. T. Pinheiro of the biological sciences department at the University of Warwick, in England, note that the toxicity of the intermediates "depends upon some as-yet-undefined structural features, and not upon their amino acid sequence. It is possible that some diseases not associated with the accumulation of amyloid fibrils may be caused by the sporadic production of this type of [intermediate] by mistakes that occur during the folding of other proteins."

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Copyright © 2002 American Chemical Society