Tetramethylpyrazine Improves Cognitive Impairment and Modifies the Hippocampal Proteome in Two Mouse Models of Alzheimer's Disease

Xianfeng Huang; Jinyao Yang; Xi Huang; Zaijun Zhang; Jianjun Liu; Liangyu Zou; Xifei Yang

doi:10.3389/fcell.2021.632843

Tetramethylpyrazine Improves Cognitive Impairment and Modifies the Hippocampal Proteome in Two Mouse Models of Alzheimer's Disease

Front Cell Dev Biol. 2021 Mar 15:9:632843. doi: 10.3389/fcell.2021.632843. eCollection 2021.

Authors

Xianfeng Huang¹, Jinyao Yang^{1

2}, Xi Huang³, Zaijun Zhang⁴, Jianjun Liu², Liangyu Zou³, Xifei Yang²

Affiliations

¹ School of Pharmacy and School of Medicine, Changzhou University, Changzhou, China.
² Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Subject of Modern Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
³ Department of Neurology, Shenzhen People's Hospital (First Affiliated Hospital of Southern University of Science and Technology), Second Clinical College, Jinan University, Shenzhen, China.
⁴ Institute of New Drug Research and Guangzhou, Key Laboratory of Innovative Chemical Drug Research in Cardio-Cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China.

Abstract

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, has no effective treatment. We studied the potential effects of tetramethylpyrazine (TMP), an alkaloid in the rhizome of Ligusticum chuanxiong Hort. used in Traditional Chinese Medicine (chuānxiong) to treat ischemic stroke, on AD progression in two AD mouse models. Eight-month-old 3xTg-AD mice received TMP treatment (10 mg/kg/d) for 1 month, and 4-month-old APP/PS1-AD mice received TMP treatment (10 mg/kg/d) for 2 months. Behavioral tests, including step-down passive avoidance (SDA), new object recognition (NOR), Morris water maze (MWM), and Contextual fear conditioning test showed that TMP significantly improved the learning and memory of the two AD-transgenic mice. In addition, TMP reduced beta-amyloid (Aß) levels and tau phosphorylation (p-tau). Venny map pointed out that 116 proteins were commonly changed in 3xTg mice vs. wild type (WT) mice and TMP-treated mice vs. -untreated mice. The same 130 proteins were commonly changed in APP/PS1 mice vs. WT mice and TMP-treated mice vs. -untreated mice. The functions of the common proteins modified by TMP in the two models were mainly involved in mitochondrial, synaptic, cytoskeleton, ATP binding, and GTP binding. Mitochondrial omics analysis revealed 21 and 20 differentially expressed mitochondrial proteins modified by TMP in 3xTg-AD mice and APP/PS1 mice, respectively. These differential proteins were located in the mitochondrial inner membrane, mitochondrial outer membrane, mitochondrial gap, and mitochondrial matrix, and the function of some proteins is closely related to oxidative phosphorylation (OXPHOS). Western-blot analysis confirmed that TMP changed the expression of OXPHOS complex proteins (sdhb, ndufa10, uqcrfs1, cox5b, atp5a) in the hippocampus of the two AD mice. Taken together, we demonstrated that TMP treatment changed the hippocampal proteome, reduced AD pathology, and reduced cognitive impairment in the two AD models. The changes might be associated with modification of the mitochondrial protein profile by TMP. The results of the study suggest that TMP can improve the symptoms of AD.

Keywords: Alzheimer's disease; OxPhoS; mitochondria; proteomics; tetramethylpyrazine.