Ellis RJ, Pinheiro TJ.
Medicine: danger--misfolding proteins.
Nature. 2002 Apr 4;416(6880):483-4.
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Our study identifies a specific form of naturally produced human amyloid beta protein, namely stable low-n oligomers, as directly interrupting a key correlate of memory and learning in a living animal. Previous research by many scientists had linked Ab in general to interruption of neural function, but precisely which form of the protein and how that occurred under natural conditions remained obscure. We now identify a specific form of naturally secreted Ab and show directly in living, anesthetized rats that it blocks long-term potentiation in the absence of monomers, protofibrils and fibrils. Thus soluble, diffusible Ab oligomers can interrupt memory circuits in the brain.
Finally, we use a chemical compound that inhibits the production of Aβ to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). This supports the potential utility of modest doses of β- or γ-secretase inhibitors in the disease.