Apoptosis induced in neuronal cells by C-terminal amyloid β-fragments is correlated with their aggregation properties in phospholipid membranes

A number of findings suggest that lipophilic monomeric A beta peptides can interact with the cellular lipid membranes. These interactions can affect the membrane integrity and result in the initiation of apoptotic cell death. The secondary structure of C-terminal A beta peptides (29-40) and the longer (29-42) variant have been investigated in solution by circular dichroism measurements. The secondary structure of lipid bound A beta (29-40) and (29-42) peptides prepared at different lipid/peptide ratio's, was Investigated by ATR-FTIR spectroscopy. Finally, the changes in secondary structure (i.e. the transition of alpha -helix to beta -sheet) of the lipid bound peptides were correlated with the induction of neurotoxic and apoptotic effects in neuronal cells. The data suggest that the C-terminal fragments of the A beta peptide induce a significant apoptotic cell death, as demonstrated by caspase-3 measurements and DNA laddering, with consistently a stronger effect of the longer A beta (29-42) variant. Moreover, the induction of apoptotic death induced by these peptides can be correlated with the secondary structure of the lipid bound amyloid beta peptides, eased on these observations, if is proposed that membrane bound aggregated A beta peptides (produced locally as the result of gamma -secretase cleavage) can accumulate and aggregate in the membrane. These membrane bound beta -sheet aggregated amyloid peptides induce neuronal apoptotic cell death.