Annexin 5 and apolipoprotein E2 protect against Alzheimer's amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site

Amyloid-β-protein (βA/4, AβP) accumulates in the brains of patients with Alzheimer's disease (AD), regardless of genetic etiology, and is thought to be the toxic principle responsible for neuronal cell death. The ε4 allele of apoE has been linked closely to earlier onset of AD and increased deposition of the amyloid peptide, regardless of the clinical status of AD, while the apoE ε2 allele is generally protective. We have previously hypothesized that the cell target for amyloid peptide might be the apoptotic signal molecule phosphatidylserine (PS). We report here that annexin 5, a specific ligand for PS, not only blocks amyloid peptide AβP[1-40] cytotoxicity, but competitively inhibits AβP[1-40]-dependent aggregation of PS liposomes. In addition, we find that apoE2, but not apoE4, can not only perform the same protective effect on cells exposed to AβP[1-40], but can also competitively inhibit PS liposome aggregation and fusion by the amyloid peptide. Altogether, the in vivo and in vitro results reported here provide fundamental insight to the process by which amyloid targets specific neurons for destruction, and suggest that PS may be a surface "receptor" site for AβP binding. These results also provide a biochemical mechanism by which the apoE ε2 allele, but not apoE ε4, can be protective towards the incidence and progression of Alzheimer's disease.