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

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.

Traditional Chinese Medicine for Post-Stroke Cognitive Impairment: A Systematic Review and Meta-Analysis

“…Tetramethylpyrazine is the main component of this herb. In terms of neuroprotection, tetramethylpyrazine reduces cognitive impairment by regulating the Janus kinase-signal transducer and activator of transcription signaling pathway, while simultaneously reducing brain edema and blood–brain barrier permeability ( Chang et al, 2007 ; Gong et al, 2019 ; Huang et al, 2021 ). The second most frequently used herb was Acorita Tatarinowii Rhizoma .…”

High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer’s disease associated with chronic platelet activation

“…Contextual fear conditioning was performed to assess associative emotional memory of mice as described previously [ 39 ]. This test has been previously used in 3 × Tg mice, demonstrating impaired performance compared to wild-type mice [ 40 ]. In the training phase, each mouse was pre-exposed to the shock chamber and allowed to explore the environment for 3 min and a subsequent foot shock (0.5mA) for 2 s. The mice were allowed to stay in the chamber for another 30s, and then, they were placed back into their home cages.…”

Regulatory mechanisms of tetramethylpyrazine on central nervous system diseases: A review

“…Evidence shows that β amyloid (Aβ) plaque deposition and hyperphosphorylated tau protein are the typical pathological changes observed in AD ( Lane et al, 2018 ). In vivo studies, TMP has been proven to improve learning and cognitive function in AD models by lowering the Aβ deposition and tau phosphorylation levels ( Huang et al, 2021 ; Zhang et al, 2021 ). The sequential cleavage of amyloid-beta precursor protein (APP) by β and γ-secretases is critical in Aβ production ( Xiaojie and Weihong, 2013 ).…”