期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 16, 期 5, 页码 10426-10442出版社
MDPI
DOI: 10.3390/ijms160510426
关键词
amyloid; endoplasmic reticulum stress; humic acid; PPAR coactivator 1; sirtuin 1
资金
- Taiwan Ministry of Science and Technology [101-2320-B-040-015-MY3]
- Ministry of Science and Technology
- Ministry of Education
- Chung Shan Medical University
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 (A) peptide in the brain. However, the role that HA contributes to A-induced cytotoxicity has not been demonstrated. In the present study, we demonstrate that HA exhibits a synergistic effect enhancing A-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 eIF2 phosphorylation. We also observed HA and A-induced cytotoxicity is associated with mitochondrial dysfunction caused by down-regulation of the Sirt1/PGC1 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 A. Our findings suggest a new mechanism by which HA can deteriorate A-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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