Mechanism and prevention of neurotoxicity caused by beta-amyloid peptides: relation to Alzheimer's disease.
In Alzheimer's disease, neurotoxic beta-amyloid peptides cause a deleterious influx of calcium ions into neurons. This increase in [Ca2+]int is expected to trigger intracellular events that eventually cause cell dysfunction and cell death. We find that the aggregated beta-amyloid peptide beta AP25-35 opens irreversibly a Ca(2+)-carrying channel, as does aggregated beta AP1-42. The opening of this channel is unaffected by DL-AP5, but it is blocked by Mg2+, CNQX and DNQX, suggesting a non-NMDA channel. External calcium enters and cytosolic calcium levels rise several-fold, as measured by fura-2 ratiometric analysis. Our findings illustrate a very early molecular event in the neurotoxicity of Alzheimer's disease. To combat the neurotoxic effect of aggregated beta-amyloid peptides, we have devised a series of very short antagonistic peptides. Using a combinatorial library of hexapeptides made from D-amino acids, we have selected peptides by their ability to complex with the tagged beta-amyloid peptide beta AP25-35. Certain of these so-called 'decoy peptides', as well as some modified decoy peptides, are able to abolish the calcium influx caused by aggregated, probably fibrillar, beta-amyloid peptides beta AP25-35 and beta AP1-42.
Blanchard
B J
BJ
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Konopka
G
G
Russell
M
M
Ingram
V M
VM
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008024:Ligands; D008274:Magnesium / Q000494:pharmacology; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D017433:Protein Structure, Secondary; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D008274:Magnesium; D002118:Calcium