Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity.
Alzheimer's disease is an age-related neurodegenerative disorder with its toxicity linked to the generation of amyloid-beta peptide (Abeta). Within the Abeta sequence, there is a systemic repeat of a GxxxG motif, which theoretical studies have suggested may be involved in both peptide aggregation and membrane perturbation, processes that have been implicated in Abeta toxicity. We synthesized modified Abeta peptides, substituting glycine for leucine residues within the GxxxG repeat motif (GSL peptides). These GSL peptides undergo beta-sheet and fibril formation at an increased rate compared with wild-type Abeta. The accelerated rate of amyloid fibril formation resulted in a decrease in the presence of small soluble oligomers such as dimeric and trimeric forms of Abeta in solution, as detected by mass spectrometry. This reduction in the presence of small soluble oligomers resulted in reduced binding to lipid membranes and attenuated toxicity for the GSL peptides. The potential role that dimer and trimer species binding to lipid plays in Abeta toxicity was further highlighted when it was observed that annexin V, a protein that inhibits Abeta toxicity, specifically inhibited Abeta dimers from binding to lipid membranes.
Hung
Lin Wai
LW
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Ciccotosto
Giuseppe D
GD
Giannakis
Eleni
E
Tew
Deborah J
DJ
Perez
Keyla
K
Masters
Colin L
CL
Cappai
Roberto
R
Wade
John D
JD
Barnham
Kevin J
KJ
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020816:Amino Acid Motifs / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D019281:Dimerization; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology
D016229:Amyloid beta-Peptides; D017304:Annexin A5; D008563:Membrane Lipids; D010446:Peptide Fragments