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Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL. Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10417-22. PubMed.
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Yale University School of Medicine
Small, soluble aggregates of the Aβ1-42 peptide are now believed to be the toxic factor that is responsible for synaptic dysfunction and eventual neuronal degeneration in Alzheimer's disease. This work adds to this consensus by showing that soluble extracts of brains from five cases of AD react with an antiserum specific for the Aβ1-42 peptide. Samples of both naturally derived Aβ1-42 peptides and synthetic versions were also found to bind in a punctate fashion to the external surfaces of culture hippocampal neurons. The authors suggest that Aβ oligomers might be binding to sites of signaling specializations, possibly related to synaptic terminals. To rule out non-specific binding, the Aβ oligomers were incubated with specific antibodies before adding them to the cultured cells. This blocked the binding of the added Aβ peptides to the cells, but this step in effect removed the oligomers from contact with the neurons and did not address whether oligomers that were available to the cells could bind non-specifically. It was also found, using the SDS gel overlay technique, that synthetic Aβ peptides bind to a number if unidentified proteins of hippocampal membrane fractions. While these preliminary observations are provocative, more direct evidence is needed to support the claim that oligomeric Aβ ligands bind in a biologically meaningful way to specific neuronal proteins that mediate signal transduction and that they are directly involved in reversible memory loss.
Northwestern University Institute for Neuroscience
Response to comment by Vincent Marchesi
Dr. Marchesi provides a thoughtful summary of our study and calls attention to an issue that's of central concern to us—specificity. AD is so memory-specific, especially early on, that one would hope to identify molecular pathogens capable of explaining this key feature of the disease. It's turning out that the property of specificity is a most intriguing aspect of ADDL nerve cell biology.
As Dr. Pascale Lacor will show in her poster at SFN-New Orleans, those hot spots of ADDL binding are neither random nor nonspecific. They actually are just what the doctor ordered—synapses. And when ADDLs get lodged in those synapses, they disrupt particular molecular mechanisms essential for memory. (Since Dr. Lacor's study is out for review, I won't comment further on its details.) The bottom line is that the specific manner in which ADDLs attack neurons can provide a synaptically localized mechanism to account for memory loss in AD.
However, even with these further interesting findings, we would, of course, agree that as always, more evidence is desirable.
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