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.
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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)
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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
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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)
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