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Previous studies suggest membrane binding is a key determinant of amyloid β (Aβ) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of Aβ42 (D-Aβ42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type Aβ42 (L-Aβ42). The results showed D- and L-Aβ42 are chemically equivalent with respect to copper binding, generation of reactive oxygen species and aggregation profiles. Cell binding studies show both peptides bound to cultured cortical neurons. However, only L-Aβ42 was neurotoxic and inhibited long term potentiation indicating L-Aβ42 requires a stereospecific target to mediate toxicity. We identified the lipid phosphatidylserine, as a potential target. Annexin V, which has very high affinity for externalized phosphatidylserine, significantly inhibited L-Aβ42 but not D-Aβ42 binding to the cultured cortical neurons and significantly rescued L-Aβ42 neurotoxicity. This suggests that Aβ mediated toxicity in Alzheimer disease is dependent upon Aβ binding to phosphatidylserine on neuronal cells.

Original publication




Journal article


Neurobiol Aging

Publication Date





235 - 248


Amyloid beta-Peptides, Animals, Annexin A5, Benzothiazoles, Biophysics, Cell Death, Cells, Cultured, Cerebral Cortex, Dose-Response Relationship, Drug, Electric Stimulation, Electron Spin Resonance Spectroscopy, Embryo, Mammalian, Hydrogen Peroxide, Long-Term Potentiation, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Neurons, Patch-Clamp Techniques, Protein Binding, Protein Conformation, Protein Structure, Secondary, Thiazoles, Time Factors, Tyrosine