ABSTRACT
Using neuronal cell cultures, the authors find that within a very few seconds of contact between aggregated Abeta1-42 and the neuronal cell there is an immediate and rapid influx of external cakcium ions via calcium-permeant AMPA-receptors, which is blocked by the specific antagonist NBQX. They consider that calcium-influx is the initiating event of Alzheimer’s Disease pathology, followed by a whole series of downstream events, including eventual cell death. Using cultured neuronal cells, the authors have developed two series of useful compounds: ten short so-called Decoy Peptides of D-amino acids, selected from a large peptide library; the selection in a High Throughput Screen of several small molecules that block and reverse Abeta fibril formation and also eliminate the Abeta-induced calcium-influx. They illustrate the effectiveness of decoy peptides and of the first HTS compound in eliminating calcium-influx. Because this HTS compound also effectively reverses Abeta fibrils, it is a good candidate for Alzheimer therapy, as are the Decoy Peptides.
