Tetramethylpyrazine Improves Cognitive Function of Alzheimer’s Disease Mice by Regulating SSTR4 Ubiquitination

Abstract

Purpose Many researches have investigated the functions of tetramethylpyrazine (TMP) in Alzheimer's disease (AD). This study aimed to discuss the underlying mechanism of TMP in AD mice. Methods TMP (200 mg/kg) was administered to 6-month-old APP/PS1 transgenic mice, and behavioral changes and hippocampal nerve injury in AD mice were detected. Apoptosis and autophagy-related protein levels were detected. Changes in gene expression before and after TMP treatment were compared using transcriptome sequencing. The effects of Cullin 4B (CUL4B) overexpression and somatostatin receptor 4 (SSTR4) silencing on AD symptoms and SSTR4 ubiquitination in APP/PS1 mice were observed. SH-SY5Y and PC12 cells were treated with 25 μmol/L Aβ 25–35 and TMP to observe cell viability, apoptosis, and autophagy. Cell viability and apoptosis were measured again after treatment with proteasome inhibitor MG132 or lysosomal inhibitor 3-mA. Results TMP treatment improved the behavioral cognition of APP/PS1 mice and improved the neuronal apoptosis and damage in brain tissue. CUL4B was significantly upregulated in APP/PS1 mouse brain tissue, and SSRT4 protein was downregulated, and the levels of CUL4B and SSRT4 were negatively correlated. TMP treatment downregulated CUL4B, inhibited SSRT4 ubiquitination and upregulated SSRT4 protein level in APP/PS1 mouse brain tissue, while CUL4B overexpression or SSRT4 silencing reversed the effect of TMP. TMP and MG132 improved the decreased activity, increased apoptosis and increased SSRT4 protein in SH-SY5Y and PC12 cells treated with Aβ 25–35 , but not 3-mA. CUL4B overexpression promoted the ubiquitination of SSTR4 in cells, which partially reversed the effect of TMP. Conclusion TMP could improve the cognitive ability of AD mice by inhibiting CUL4B expression and the ubiquitination degradation of SSTR, and alleviating neuronal apoptosis and injury. This study may offer a new therapeutic option for AD treatment.

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

“…In vivo, TMP treatment improved the learning and memory function, attenuating AD mice’s cognitive impairment. The potential mechanism might be related to reducing the ubiquitination of SSTR4, thus increasing its levels in the system ( Weng et al, 2021 ). Apart from these, researchers have designed the ligustrazine phosphate (LP) transdermal ethosomal system, and evaluated the effect of LP on AD in scopolamine-induced amnesia rats.…”

Medicinal Herbs and Their Derived Ingredients Protect against Cognitive Decline in In Vivo Models of Alzheimer’s Disease

“…Somatostatin receptor 4 (SSTR4), mainly distributed in the cortex and hippocampus, is crucial in learning and memory. SSTR4 can upregulate Aβ-degrading enzyme expression in the hippocampus, whereas ubiquitin-mediated degradation of SSTR4 initiates neuronal apoptosis in AD pathogenesis [ 8 ]. Cullin 4B (CUL4B) overexpression promotes SSTR4 ubiquitination, resulting in AD exacerbation [ 8 , 136 ].…”

“…SSTR4 can upregulate Aβ-degrading enzyme expression in the hippocampus, whereas ubiquitin-mediated degradation of SSTR4 initiates neuronal apoptosis in AD pathogenesis [ 8 ]. Cullin 4B (CUL4B) overexpression promotes SSTR4 ubiquitination, resulting in AD exacerbation [ 8 , 136 ]. In 2020, Weng et al demonstrated that tetramethylpyrazine, extracted from Ligusticum wallichii , attenuates cognitive impairment by downregulating CUL4B/SSTR4-mediated apoptotic signaling in the hippocampus at 30 days in APP/PS1 mice [ 8 ].…”

“…Clinical research has demonstrated that metabolic diseases such as obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) and unhealthy lifestyle habits such as smoking, stress, and sleep disorders are closely associated with sporadic AD development [ 3 , 4 , 5 ]. Over 45 million people worldwide have AD, and people aged >65 years demonstrate a high prevalence of AD (7–10%), leading to death within 3–9 years after confirmed diagnosis [ 5 , 6 , 7 , 8 ]. AD is currently ranked as fifth leading cause of death among the elderly population in the United States [ 9 ].…”

Increasing brain glucose metabolism by ligustrazine piperazine ameliorates cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice

“…Ligustrazine has been shown to activate PPARγ and promote mitophagy by inducing Parkin translocation to the mitochondria [ 38 , 40 ]. Importantly, ligustrazine improves cognitive impairment in rodent models of AD [ 13 , 35 ], suggesting that ligustrazine may become a novel drug candidate for the treatment of AD. However, the short elimination half-life of ligustrazine seriously limits its application in clinical practice [ 41 ].…”