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