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Danggui Buxue decoction ameliorates mitochondrial biogenesis and cognitive deficits through upregulating histone H4 lysine 12 acetylation in APP/PS1 mice.

Authors :
Chai, Gao-shang
Gong, Juan
Wu, Jia-jun
Ma, Rui-kun
Zhu, Jun
Jia, Dong-dong
Zhang, Yu-qi
Zhai, Xiao-run
Sun, Hong-xu
Nie, Yun juan
Zhao, Peng
Xu, Yi-liang
Yu, Hai tao
Source :
Journal of Ethnopharmacology. Sep2023, Vol. 313, pN.PAG-N.PAG. 1p.
Publication Year :
2023

Abstract

Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aβ accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment. Treated by DBD, the level of phosphorylation of APP was downregulated to cause Aβ deposition to decrease in APP/PS1 mice. Meanwhile, DBD restored mitochondrial biogenesis by the HDAC2/H4K12 acetylation/PGC-1α pathway and improved synaptic plasticity through the HDAC2/H4K12 acetylation/GluN2B pathway. In conclusion, DBD could ameliorate cognitive deficits in APP/PS1 mice. [Display omitted] • DBD ameliorated cognitive deficits in APP/PS1 mice. • DBD attenuated Aβ deposition by decreasing the phosphorylation of APP at the Thr668 level. • DBD restored mitochondrial biogenesis by the HDAC2/H4K12 acetylation/PGC-1α pathway. • DBD improved synaptic plasticity through the HDAC2/H4K12 acetylation/GluN2B pathway. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
03788741
Volume :
313
Database :
Academic Search Index
Journal :
Journal of Ethnopharmacology
Publication Type :
Academic Journal
Accession number :
163794746
Full Text :
https://doi.org/10.1016/j.jep.2023.116554