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The Journal of Neuroscience, November 12, 2008, 28(46):11950-11958; doi:10.1523/JNEUROSCI.3916-08.2008

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Neurobiology of Disease
Amyloid-β Peptide (Aβ) Neurotoxicity Is Modulated by the Rate of Peptide Aggregation: Aβ Dimers and Trimers Correlate with Neurotoxicity

Lin Wai Hung,^1,2,3,4 Giuseppe D. Ciccotosto,^1,2,4 Eleni Giannakis,³ Deborah J. Tew,^1,2,4 Keyla Perez,^1,2,4 Colin L. Masters,^2,4 Roberto Cappai,^1,2,4 John D. Wade,³ and Kevin J. Barnham^1,2,4

¹Department of Pathology, ²Bio21 Molecular Science and Biotechnology Institute, and ³The Howard Florey Institute of Physiology and Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia, and ⁴Mental Health Research Institute, Parkville, Victoria 3052, Australia

Correspondence should be addressed to Kevin J. Barnham, Level 4, Bio21 Institute, 30 Flemington Road, Parkville, Victoria 3010, Australia. Email: kbarnham{at}unimelb.edu.au

Alzheimer's disease is an age-related neurodegenerative disorder with its toxicity linked to the generation of amyloid-β peptide (Aβ). Within the Aβ 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 Aβ toxicity. We synthesized modified Aβ peptides, substituting glycine for leucine residues within the GxxxG repeat motif (GSL peptides). These GSL peptides undergo β-sheet and fibril formation at an increased rate compared with wild-type Aβ. 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 Aβ 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 Aβ toxicity was further highlighted when it was observed that annexin V, a protein that inhibits Aβ toxicity, specifically inhibited Aβ dimers from binding to lipid membranes.

Key words: Alzheimer's disease; amyloid-β; small soluble oligomers; GxxxG; aggregation; neurotoxicity; lipid

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Received Aug. 18, 2008; revised Sept. 22, 2008; accepted Sept. 22, 2008.

Correspondence should be addressed to Kevin J. Barnham, Level 4, Bio21 Institute, 30 Flemington Road, Parkville, Victoria 3010, Australia. Email: kbarnham{at}unimelb.edu.au

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