TY - JOUR
T1 - Mechanism and prevention of neurotoxicity caused by β-amyloid peptides
T2 - Relation to Alzheimer's disease
AU - Blanchard, Barbara J.
AU - Konopka, Genevieve
AU - Russell, Margaret
AU - Ingram, Vernon M.
N1 - Funding Information:
Helpful discussions with our colleagues J. Butler, C.-H. Chen, A. Hiniker, and R. Rabindran are gladly acknowledged. N. Rafizadeh helped to edit the manuscript. The research was supported by the Baum Fund for Alzheimer Research, by the John and Dorothy Wilson Fund, by the Johanna and Kurt Immerwahr Fund for Alzheimer Research, and by MIT's Undergraduate Research Opportunities Program.
PY - 1997/11/21
Y1 - 1997/11/21
N2 - In Alzheimer's disease, neurotoxic β-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 β- amyloid peptide βAP25-35 opens irreversibly a Ca2+-carrying channel, as does aggregated βAP1-42. 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 β-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 β-amyloid peptide βAP25-35. 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, β-amyloid peptides βAP25-35 and βAP1-42.
AB - In Alzheimer's disease, neurotoxic β-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 β- amyloid peptide βAP25-35 opens irreversibly a Ca2+-carrying channel, as does aggregated βAP1-42. 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 β-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 β-amyloid peptide βAP25-35. 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, β-amyloid peptides βAP25-35 and βAP1-42.
KW - Calcium homeostasis
KW - Calcium ion channel
KW - Calcium ion concentration
KW - Decoy peptide
KW - HNT neuron
KW - Non-NMDA channel
KW - β-Amyloid fibril
KW - β-Amyloid peptide
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U2 - 10.1016/S0006-8993(97)01003-2
DO - 10.1016/S0006-8993(97)01003-2
M3 - Article
C2 - 9439794
AN - SCOPUS:0031445940
SN - 0006-8993
VL - 776
SP - 40
EP - 50
JO - Brain Research
JF - Brain Research
IS - 1-2
ER -