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Int. J. Mol. Sci. 2015, 16(5), 10426-10442; doi:10.3390/ijms160510426

Humic Acid Increases Amyloid β-Induced Cytotoxicity by Induction of ER Stress in Human SK-N-MC Neuronal Cells

1
Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
2
Department of Life Sciences and Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40227, Taiwan
3
Institute of Microbiology & Immunology, Chung Shan Medical University, Taichung 40201, Taiwan
4
Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
5
Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: G. Jean Harry
Received: 25 January 2015 / Revised: 23 April 2015 / Accepted: 4 May 2015 / Published: 7 May 2015
(This article belongs to the Special Issue Molecular Research in Neurotoxicology)
View Full-Text   |   Download PDF [3753 KB, uploaded 7 May 2015]   |  

Abstract

Humic acid (HA) is a possible etiological factor associated with for several vascular diseases. It is known that vascular risk factors can directly increase the susceptibility to Alzheimer’s disease (AD), which is a neurodegenerative disorder due to accumulation of amyloid β (Aβ) peptide in the brain. However, the role that HA contributes to Aβ-induced cytotoxicity has not been demonstrated. In the present study, we demonstrate that HA exhibits a synergistic effect enhancing Aβ-induced cytotoxicity in cultured human SK-N-MC neuronal cells. Furthermore, this deterioration was mediated through the activation of endoplasmic reticulum (ER) stress by stimulating PERK and eIF2α phosphorylation. We also observed HA and Aβ-induced cytotoxicity is associated with mitochondrial dysfunction caused by down-regulation of the Sirt1/PGC1α pathway, while in contrast, treating the cells with the ER stress inhibitor Salubrinal, or over-expression of Sirt1 significantly reduced loss of cell viability by HA and Aβ. Our findings suggest a new mechanism by which HA can deteriorate Aβ-induced cytotoxicity through modulation of ER stress, which may provide significant insights into the pathogenesis of AD co-occurring with vascular injury. View Full-Text
Keywords: amyloid β; endoplasmic reticulum stress; humic acid; PPARγ coactivator 1α; sirtuin 1 amyloid β; endoplasmic reticulum stress; humic acid; PPARγ coactivator 1α; sirtuin 1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Li, H.-H.; Lu, F.-J.; Hung, H.-C.; Liu, G.-Y.; Lai, T.-J.; Lin, C.-L. Humic Acid Increases Amyloid β-Induced Cytotoxicity by Induction of ER Stress in Human SK-N-MC Neuronal Cells. Int. J. Mol. Sci. 2015, 16, 10426-10442.

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