The N-Methylated Peptide SEN304 Powerfully Inhibits A尾(1鈥?2) Toxicity by Perturbing Oligomer Formation
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- 作者：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
- 刊名：Biochemistry
- 出版年：2012
- 出版时间：October 23, 2012
- 年：2012
- 卷：51
- 期：42
- 页码：8338-8352
- 全文大小：655K
- 年卷期：v.51,no.42(October 23, 2012)
- ISSN：1520-4995
文摘
Oligomeric forms of 尾-amyloid (A尾) have potent neurotoxic activity and are the primary cause of neuronal injury and cell death in Alzheimer鈥檚 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 A尾 aggregation and toxicity, shown primarily by thioflavin T fluorescence and MTT (Kokkoni, N. et al. (2006) N-Methylated peptide inhibitors of 尾-amyloid aggregation and toxicity. Optimisation of inhibitor structure. Biochemistry45, 9906鈥?918). Here we extensively characterize how SEN304 affects A尾(1鈥?2) 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 A尾(1鈥?2) toxicity, particularly effective at preventing A尾 inhibition of long-term potentiation. It can bind directly to A尾(1鈥?2), delay 尾-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 A尾 oligomers. It is therefore a promising lead compound for Alzheimer鈥檚 disease.