Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity

• Published in: Neurobiology of aging 2011-02, Vol.32 (2), p.235-248
• Main Authors: Ciccotosto, Giuseppe D, Tew, Deborah J, Drew, Simon C, Smith, Danielle G, Johanssen, Timothy, Lal, Varsha, Lau, Tong-Lay, Perez, Keyla, Curtain, Cyril C, Wade, John D, Separovic, Frances, Masters, Colin L, Smith, Jeffrey P, Barnham, Kevin J, Cappai, Roberto
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - toxicity; Animals; Annexin A5 - metabolism; Annexin V; Biological and medical sciences; Biophysics; Cell Death - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Chiral; Cortex; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development. Senescence. Regeneration. Transplantation; Dose-Response Relationship, Drug; Electric Stimulation - methods; Electron Spin Resonance Spectroscopy; Embryo, Mammalian; Fundamental and applied biological sciences. Psychology; Hydrogen Peroxide - metabolism; Internal Medicine; Long term potentiation; Long-Term Potentiation - drug effects; Medical sciences; Membrane phospholipid; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission - methods; Neurology; Neurons - drug effects; Neurons - ultrastructure; Neurotoxicity; Patch-Clamp Techniques; Protein Binding - drug effects; Protein Conformation; Protein Structure, Secondary; Thiazoles - metabolism; Time Factors; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2009.02.018

Abstract 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.