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

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.

• Authors: Hsin-Hua Li, Fung-Jou Lu, Hui-Chih Hung, Guang-Yaw Liu, Te-Jen Lai, Chih-Li Lin
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 5 Pg. 10426-42 (May 07 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 25961951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cinnamates
• Humic Substances
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Transcription Factors
• salubrinal
• PERK kinase
• eIF-2 Kinase
• SIRT1 protein, human
• Sirtuin 1
• Thiourea

Topics

• Amyloid beta-Peptides (toxicity)
• Cell Line, Tumor
• Cinnamates (pharmacology)
• Endoplasmic Reticulum Stress
• Humans
• Humic Substances (toxicity)
• Neurons (drug effects, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Sirtuin 1 (metabolism)
• Thiourea (analogs & derivatives, pharmacology)
• Transcription Factors (metabolism)
• eIF-2 Kinase (metabolism)