Stereospecific interactions are necessary for Alzheimer's disease amyloid-beta toxicity

Abstract

Alzheimer disease (AD) is the major cause of age-related dementia. AD is characterized by the abnormal accumulation of the amyloid-beta peptide (Abeta) into insoluble aggregates known as plaques. Abeta is derived from the amyloid precursor protein (APP), with Abeta40 and Abeta42 the dominant peptide species. The precise mechanism of Abeta-induced neuronal toxicity remains unresolved. Since Abeta contains part of the putative transmembrane domain of the APP, the mechanism of Abtea mediated neurotoxicity may involve interactions with the cell membrane. We and others have previously reported that Abeta neurotoxicity is correlated with an increased affinity for the neuronal plasma membrane. Potential molecular targets on the cell membrane for Abeta includes lipids, proteoglycans, and proteins. To test if Abeta toxicity and cell membrane binding was receptor mediated i.e. required a stereospecific interaction. We synthesized D- and L-handed versions of Abeta42 because in the absence of a chiral environment, both the variants would behave identically and as such if a receptor was not required for toxicity then it would be expected that both peptides would be equally toxic. Various biophysical, membrane binding and neurotoxic properties were examined. The results showed D-Abeta42 and L-Abeta42 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-Abeta42 was neurotoxic and inhibited long term potentiation indicating L-Abeta42 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- but not D-Abeta42 binding to the cultured cortical neurons and significantly rescued L-Abeta42 neurotoxicity. This suggests that Abeta mediated toxicity in Alzheimer disease is dependent upon Abeta binding to phosphatidylserine on neuronal cells.