Apoptosis induced in neuronal cells by C-terminal amyloid beta-fragments is correlated with their aggregation properties in phospholipid membranes.
A number of findings suggest that lipophilic monomeric Abeta 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 Abeta peptides (29-40) and the longer (29-42) variant have been investigated in solution by circular dichroism measurements. The secondary structure of lipid bound Abeta (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 Abeta peptide induce a significant apoptotic cell death, as demonstrated by caspase-3 measurements and DNA laddering, with consistently a stronger effect of the longer Abeta (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. Based on these observations, it is proposed that membrane bound aggregated Abeta 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.
Demeester
N
N
Department of Biochemistry, University Ghent, Gent, Belgium.
Baier
G
G
Enzinger
C
C
Goethals
M
M
Vandekerckhove
J
J
Rosseneu
M
M
Labeur
C
C
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D008051:Lipid Bilayers / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D010743:Phospholipids / Q000737:chemistry; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010446:Peptide Fragments; D010743:Phospholipids; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases