title: Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity.
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.
authors.affiliation: Department of Pathology, The University of Melbourne, VIC 3010, Australia.
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Ciccotosto
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Tew
authors.forename: Simon C
authors.initials: SC
authors.lastname: Drew
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Smith
authors.forename: Timothy
authors.initials: T
authors.lastname: Johanssen
authors.forename: Varsha
authors.initials: V
authors.lastname: Lal
authors.forename: Tong-Lay
authors.initials: TL
authors.lastname: Lau
authors.forename: Keyla
authors.initials: K
authors.lastname: Perez
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Frances
authors.initials: F
authors.lastname: Separovic
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Smith
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai