| STUDY |
AGGREGATES OF MISFOLDED proteins are characteristic of Alzheimers disease. But do these AMYLOID FIBRILS or PLAQUES cause the disease? Evidence is accumulating that the plaques may be less harmful than the SMALLER INTERMEDIATES (PRECURSOR) that combine to form them. Plaques that develop in the brains of AD patients are built up from fibrils composed of > hundreds AMYLOID-BETA PEPTIDE (A-Beta) molecules. Now researchers have demonstrated that OLIGOMERS composed of just a few A-Beta molecules – rather than the LARGER fibrils or individual A-Be ta monomers – may be the most dangerous entities for brain cells The team which is the first to examine the effect of defined oligomers in vivo, injected human A-Beta monomers & 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 & memory function, capabilities that are degraded in AD patients “This is the first study that connects in vivo synaptotoxicity with a chemically defined form of natural A-Beta” “It puts the smoking gun in the hands of the oligomers. Fibrils may still participate in the progression of the disease, probably as a reservoir of oligomers. The team also determined that the GAMMA-SECRETASE INHIBITORS known as DAPM & MWIII-20 offer a prototype approach for treating protein- folding disorders. |
| COMMENTS |
Ellis R. John. University of Warwick. Biological Sciences Dept. Pinheiro Teresa J.T. University of Warwick. Biological Sciences Dept. Note that the toxicity of the intermediates “depends upon some as-yet-undefin ed structural features, & not upon their aminoacid seq. 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” |
| UPDATE | 04.02 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
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