Abstract
Endoplasmic reticulum stress (ER stress) plays a critical role in neuronal apoptosis along with the aggravation of Alzheimer’s disease (AD). Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that is involved in regulating ER stress in Alzheimer’s disease (AD), therefore, this protein could be a promising therapeutic target for AD. Vanadium compounds, such as vanadyl acetylacetonate, sodium metavanadate and bis(maltolato)oxovanadium, are well-known as puissant PPARγ modulators. Thus, we are curious whether bis(ethylmaltolato)oxidovanadium (IV) (BEOV) can ameliorate ER stress and subsequent neuronal apoptosis by regulating PPARγ in AD models. To this end, we determined the effect of BEOV on behavioral performance, ER stress and neuronal apoptosis in the triple transgenic mouse AD model (3×Tg-AD). Our results showed that BEOV improved cognitive abilities and reduced the ER stress- and apoptosis-associated proteins in the brains of 3×Tg-AD mice. In vitro administration of BEOV in primary hippocampal neurons and N2asw cells achieved similar results in repressing ER stress. In addition, cotreatment with GW9662 (an antagonist of PPARγ) effectively blocked these neuroprotective effects of BEOV, which provided strong evidence that PPARγ-dependent signaling plays a key role in protecting against ER stress and neuronal apoptosis in AD. In conclusion, our data demonstrated that BEOV alleviated neuronal apoptosis triggered by ER stress by regulating PPARγ in a 3×Tg-AD model.
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Acknowledgements
We would like to thank the Instrumental Analysis Center of Shenzhen University (Xili Campus) for offering access to the experimental instruments.
Funding
This study was financially supported by grants from the National Natural Science Foundation of China (21877081; 31700919), Shenzhen Science and Technology Innovation Commission [JCYJ20180507182417779], Shenzhen-Hong Kong Institute of brain Science-Shenzhen Fundamental Research institutions (No. 2019SHIBS0003).
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QL and NL designed the study. ZJH, JXS, CW, HZZ, XXL and WX performed the majority of behavioral experiments and analyzed the data. ZJH and XQL performed the in vitro experiments and analyzed the data. NL and ZJH co-wrote the manuscript. NL, JZN and XBD contributed in interpreting the results. All authors reviewed and concurred with the final manuscript.
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Animal experiments were performed in compliance with the institutional guidelines at Shenzhen University. The protocol was approved by the Laboratory Animal Ethics Committee of Shenzhen University (Permit Number: AEWC-20140615-002).
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He, Z., Song, J., Li, X. et al. Bis(ethylmaltolato)oxidovanadium (IV) alleviates neuronal apoptosis through regulating peroxisome proliferator-activated receptor γ in a triple transgenic animal model of Alzheimer’s disease. J Biol Inorg Chem 26, 551–568 (2021). https://doi.org/10.1007/s00775-021-01874-8
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DOI: https://doi.org/10.1007/s00775-021-01874-8