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Article type: Research Article
Authors: Du, Xue-tinga; b; 1 | Wang, Lia; 1 | Wang, Yu-jiongb | Andreasen, Mariac | Zhan, Da-weid | Feng, Yinga | Li, Minb | Zhao, Mina | Otzen, Danielc | Xue, Dia; b | Yang, Yanga; b | Liu, Rui-tiana; *
Affiliations: [a] Tsinghua University, School of Medicine, Haidian District, Beijing, China | [b] School of Life Sciences, Ningxia University, Yinchuan, China | [c] Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Aarhus C, Denmark | [d] First Hospital Affiliated to General Hospital of the Chinese People's Liberation Army, Beijing, China
Correspondence: [*] Correspondence to: Rui-tian Liu, Tsinghua University, School of Medicine, Haidian District, Beijing, 100084 China. Tel.: +86 010 62797102; Fax: +86 010 62792995; E-mail: [email protected].
Note: [1] These authors contributed equally to the work.
Abstract: Amyloid-β (Aβ40/42) aggregates containing the cross-β-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of Aβ40/42, Aβ1-16, does not aggregate, and is not cytotoxic. However, we here show that Aβ1-16 can aggregate, and form cytotoxic aggregates containing β-turns and regular non-amyloid β-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence Aβ1-16 aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in Aβ1-16 may play a role in this aggregation. Our MTT results showed that Aβ1-16 monomers or oligomers were toxic to SH-SY5Y cells, but Aβ1-16 fibrils exhibited less cytotoxicity. Our studies also indicate that Aβ1-16 aggregates can increase the formation of reactive oxygen species and nitric oxide, induce the loss of calcium homeostasis, and incur the microglial production of TNF-α and IL-4. Thus, our findings suggest that Aβ1-16 may contribute to AD pathogenesis.
Keywords: Aggregation, Alzheimer's disease, amyloid-β, neurotoxicity
DOI: 10.3233/JAD-2011-110476
Journal: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 401-413, 2011
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