期刊
FRONTIERS IN NEUROSCIENCE
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2016.00598
关键词
Alzheimer's disease; formaldehyde; resveratrol; tau protein; GSK-3 beta; CaMKII; PP2A
资金
- National Program for Key Basic Research Projects (973 Programs) [2015CB755605, 2012CB825503, 2012CBA01304]
- Strategic Priority Research Program of the CAS [XDB02020005]
- Key Research Program of the Chinese Academy of Sciences
- Selected Frontier Scientific Significant Breakthrough Project of the CAS
- Key Program of the Chinese Academy of Sciences [KZCC-EW-103-2]
- Training Program of the Major Research Plan of the National Natural Science Foundation of China [91332120]
- National Natural Science Foundation of China [81471312, 31271167, 81271495, 81460352]
- Yunnan Provincial Project to Attract One-hundred Exceptional Talents From Overseas
- Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province [2014FA047]
Recent studies have demonstrated that formaldehyde (FA)-induced neurotoxicity is important in the pathogenesis of Alzheimer's disease (AD). Elevated levels of FA have been associated with memory impairments and the main hallmarks of AD pathology, including beta-amyloid plaques, tau protein hyperphosphorylation, and neuronal loss. Resveratrol (Res), as a polyphenol anti-oxidant, has been considered to have therapeutic potential for the treatment of AD. However, it has not been elucidated whether Res can exert its neuroprotective effects against FA-induced neuronal damages related to AD pathology. To answer this question, the effects of Res were investigated on Neuro-2a (N2a) cells prior to and after FA exposure. The experiments found that pre-treatment with Res significantly decreased FA-induced cytotoxicity, reduced cell apoptosis rates, and inhibited the hyperphosphorylation of tau protein at Thr181 in a dose-dependent manner. Further tests revealed that this effect was associated with the suppression of glycogen synthase kinase (GSK-3 beta) and calmodulin-dependent protein kinase II (CaMKII) activities, both of which are important kinases for tau protein hyperphosphorylation. In addition, Res was found to increase the activity of phosphoseryl/phosphothreonyl protein phosphatase-2A (PP2A). In summary, these findings provide evidence that Res protects N2a cells from FA-induced damages and suggests that inhibition of GSK-3 beta and CaMKII and the activation of PP2A by Res protect against the hyperphosphorylation and/or mediates the dephosphorylation of tau protein, respectively. These possible mechanisms underlying the neuroprotective effects of Res against FA-induced damages provide another perspective on AD treatment via inhibition of tau protein hyperhosphorylation.
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