The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation

Hozefa Amijee, Clive Bate, Alun Williams, Jasmeet Virdee, Ross Jeggo, David Spanswick, David I C Scopes, J. Mark Treherne, Sonia Mazzitelli, Ross Chawner, Claire E. Eyers, Andrew J. Doig

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Abstract

Oligomeric forms of β-amyloid (Aβ) have potent neurotoxic activity and are the primary cause of neuronal injury and cell death in Alzheimer's disease (AD). Compounds that perturb oligomer formation or structure may therefore be therapeutic for AD. We previously reported that d-[(chGly)-(Tyr)-(chGly)-(chGly)-(mLeu)]-NH2 (SEN304) is able to inhibit Aβ aggregation and toxicity, shown primarily by thioflavin T fluorescence and MTT (Kokkoni, N. et al. (2006) N-Methylated peptide inhibitors of β-amyloid aggregation and toxicity. Optimisation of inhibitor structure. Biochemistry45, 9906-9918). Here we extensively characterize how SEN304 affects Aβ(1-42) aggregation and toxicity, using biophysical assays (thioflavin T, circular dichroism, SDS-PAGE, size exclusion chromatography, surface plasmon resonance, traveling wave ion mobility mass spectrometry, electron microscopy, ELISA), toxicity assays in cell culture (MTT and lactate dehydrogenase in human SH-SHY5Y cells, mouse neuronal cell death and synaptophysin) and long-term potentiation in a rat hippocampal brain slice. These data, with dose response curves, show that SEN304 is a powerful inhibitor of Aβ(1-42) toxicity, particularly effective at preventing Aβ inhibition of long-term potentiation. It can bind directly to Aβ(1-42), delay β-sheet formation and promote aggregation of toxic oligomers into a nontoxic form, with a different morphology that cannot bind thioflavin T. SEN304 appears to work by inducing aggregation, and hence removal, of Aβ oligomers. It is therefore a promising lead compound for Alzheimer's disease.

Original languageEnglish
Pages (from-to)8338-8352
Number of pages15
JournalBiochemistry
Volume51
Issue number42
DOIs
Publication statusPublished - Oct 23 2012

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Oligomers
Toxicity
Agglomeration
Peptides
Alzheimer Disease
Long-Term Potentiation
Cell death
Amyloid
Assays
Cell Death
Lead compounds
Synaptophysin
Surface Plasmon Resonance
Size exclusion chromatography
Poisons
Dichroism
Surface plasmon resonance
Circular Dichroism
L-Lactate Dehydrogenase
Cell culture

ASJC Scopus subject areas

  • Biochemistry

Cite this

Amijee, H., Bate, C., Williams, A., Virdee, J., Jeggo, R., Spanswick, D., ... Doig, A. J. (2012). The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation. Biochemistry, 51(42), 8338-8352. https://doi.org/10.1021/bi300415v

The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation. / Amijee, Hozefa; Bate, Clive; Williams, Alun; Virdee, Jasmeet; Jeggo, Ross; Spanswick, David; Scopes, David I C; Treherne, J. Mark; Mazzitelli, Sonia; Chawner, Ross; Eyers, Claire E.; Doig, Andrew J.

In: Biochemistry, Vol. 51, No. 42, 23.10.2012, p. 8338-8352.

Research output: Contribution to journalArticle

Amijee, H, Bate, C, Williams, A, Virdee, J, Jeggo, R, Spanswick, D, Scopes, DIC, Treherne, JM, Mazzitelli, S, Chawner, R, Eyers, CE & Doig, AJ 2012, 'The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation', Biochemistry, vol. 51, no. 42, pp. 8338-8352. https://doi.org/10.1021/bi300415v
Amijee H, Bate C, Williams A, Virdee J, Jeggo R, Spanswick D et al. The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation. Biochemistry. 2012 Oct 23;51(42):8338-8352. https://doi.org/10.1021/bi300415v
Amijee, Hozefa ; Bate, Clive ; Williams, Alun ; Virdee, Jasmeet ; Jeggo, Ross ; Spanswick, David ; Scopes, David I C ; Treherne, J. Mark ; Mazzitelli, Sonia ; Chawner, Ross ; Eyers, Claire E. ; Doig, Andrew J. / The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation. In: Biochemistry. 2012 ; Vol. 51, No. 42. pp. 8338-8352.
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AU - Jeggo, Ross

AU - Spanswick, David

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