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A number of findings suggest that lipophilic monomeric Aβ 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 Aβ peptides (29-40) and the longer (29-42) variant have been investigated in solution by circular dichroism measurements. The secondary structure of lipid bound Aβ (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 α-helix to β-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 Aβ peptide induce a significant apoptotic cell death, as demonstrated by caspase-3 measurements and DNA laddering, with consistently a stronger effect of the longer Aβ (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 β peptides. Based on these observations, it is proposed that membrane bound aggregated Aβ peptides (produced locally as the result of γ-secretase cleavage) can accumulate and aggregate in the membrane. These membrane bound β-sheet aggregated amyloid peptides induce neuronal apoptotic cell death. [ABSTRACT FROM AUTHOR]