Abstract
T-006, a small-molecule compound derived from tetramethylpyrazine (TMP), has potential for the treatment of neurological diseases. In order to investigate the effect of T-006 prophylactic treatment on an Alzheimer’s disease (AD) model and identify the target of T-006, we intragastrically administered T-006 (3 mg/kg) to Alzheimer’s disease (AD) transgenic mice (APP/PS1-2xTg and APP/PS1/Tau-3xTg) for 6 and 8 months, respectively. T-006 improved cognitive ability after long-term administration in two AD mouse models and targeted mitochondrial-related protein alpha-F1-ATP synthase (ATP5A). T-006 significantly reduced the expression of phosphorylated-tau, total tau, and APP while increasing the expression of synapse-associated proteins in 3xTg mice. In addition, T-006 modulated the JNK and mTOR-ULK1 pathways to reduce both p-tau and total tau levels. Our data suggested that T-006 mitigated cognitive decline primarily by reducing the p-tau and total tau levels in 3xTg mice, supporting further investigation into its development as a candidate drug for AD treatment.
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Data Availability
All data generated or analysed during this study are included in this published article.
Abbreviations
- AD:
-
Alzheimer’s disease
- APP:
-
Amyloid precursor protein
- NFTs:
-
Neurofibrillary tangles
- Aβ:
-
β-Amyloid
- 2xTg:
-
APP/PS1
- 3xTg:
-
APP/PS1/Tau
- PS1:
-
Presenilin 1
- ATP5A:
-
Alpha-F1-ATP synthase
- DARTS:
-
Drug affinity responsive target stability
- ATP synthase:
-
Complex V of electron transfer chain (ETC)
- mTOR:
-
Mammalian target of rapamycin
- TMP:
-
Tetramethylpyrazine
- MWM:
-
Morris water maze
- NOR:
-
Novel object recognition
- SYP:
-
Synaptophysin
- PSD95:
-
Postsynaptic density protein 95
- i.g:
-
Intragastric administration
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Acknowledgments
We thank Linda Wang for editing this manuscript.
Funding
This work was supported in part by grants from the Natural Science Fund of China (81803512, 81872842, 31861163001 and U1801287) and the Natural Science Foundation of Guangdong Province (2018A030310562). We would also like to thank Ms. Linda Wang for editing this manuscript.
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Guiliang Zhang, Jiahui Wu, Zhiyang Su, Chunhui Huang, Jiehong Cheng, and Zeyu Zhu: development or design of methodology, data curation; Guiliang Zhang and Haiyun Chen: writing—original draft preparation; Xifei Yang, Baojian Guo, Liangmiao Wu, Zaijun Zhang, Gaoxiao Zhang, Haiyun Chen, Yewei Sun and Yuqiang Wang: investigation; Xifei Yang, Baojian Guo, Liangmiao Wu, Zaijun Zhang and Yuqiang Wang: investigation and supervision; Haiyun Chen, Yewei Sun, Zaijun Zhang and Yuqiang Wang: supervision, writing—reviewing and editing.
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Zhang, G., Wu, J., Huang, C. et al. The Tetramethylpyrazine Analogue T-006 Alleviates Cognitive Deficits by Inhibition of Tau Expression and Phosphorylation in Transgenic Mice Modeling Alzheimer’s Disease. J Mol Neurosci 71, 1456–1466 (2021). https://doi.org/10.1007/s12031-020-01762-x
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DOI: https://doi.org/10.1007/s12031-020-01762-x