Research progress on the regulation of tau protein hyperphosphorylation in Alzheimer’s disease by traditional Chinese medicine
At present, the global population pattern is showing an aging trend, and the incidence of Alzheimer’s disease (AD) is increasing year by year. In 30 years, the total number of elderly dementia patients worldwide will reach 138 million, with the vast majority being AD patients. Affected by the current novel coronavirus epidemic, the number of nursing workers for AD patients has declined sharply, increasing the pressure of the huge group of AD patients on individuals, families and the whole society. The onset and progression of AD are not yet controllable, and progressive emotional and cognitive disorders, as well as memory decline, are its significant clinical manifestations. Overphosphorylation of tau protein is the main factor leading to neurofibrillary tangles (NTFs), and NFTs are the main pathological feature of AD. Tau protein is a microtubule associated protein that binds to microtubules to maintain their structural stability and physiological function. The threonine (Thr), serine (Ser), and tyrosine (Tyr) located on the tau protein are called phosphorylation sites, which undergo phosphorylation under the action of kinases to form phosphorylated tau protein; Phosphorylated tau protein dissociates from bound microtubules, leading to decreased microtubule stability and causing cytoskeleton collapse. The dissociated phosphorylated tau protein forms a double helix structure and subsequently forms NFTs; Phosphatase can remove the phosphate groups on phosphorylated tau protein and restore its physiological function (see Figure 1). In summary, the phosphorylation level of tau protein depends on the joint regulation of kinase and phosphatase.

AD belongs to the category of “dementia” in traditional Chinese medicine, which has the characteristics of syndrome differentiation and treatment, holistic concept, and combination of disease and syndrome. The use of traditional Chinese medicine has unique advantages in the prevention and treatment of AD. According to existing clinical and animal studies, traditional Chinese medicine has the advantage of inhibiting tau protein hyperphosphorylation through multiple pathways in the prevention and treatment of Alzheimer’s disease (see Tables 1 and 2). For example, traditional Chinese medicine regulates the activity of kinases and phosphatases to reduce tau protein phosphorylation levels, thereby slowing down the formation of NFTs. Therefore, this article explores the mechanism of traditional Chinese medicine intervention in tau protein hyperphosphorylation and prevention and treatment of AD from the perspective of regulating kinases and phosphatases.

 

Although there is currently no mature way to intervene in the onset and progression of Alzheimer’s disease, a large number of clinical, animal, and cell experiments with traditional Chinese medicine have confirmed that it has a certain effect on intervening in tau protein hyperphosphorylation in Alzheimer’s disease. Traditional Chinese Medicine believes that AD is located in the brain and is closely related to the four organs of the heart, liver, spleen, and kidneys. Under the guidance of the heart, the spleen transports nutrients, the liver regulates the body, the kidneys store essence, and the various organs cooperate to ensure the normal functioning of the nervous system. It has been confirmed that a series of herbal formulas with the effects of nourishing liver and kidney, nourishing qi and promoting blood circulation, nourishing marrow and intelligence, clearing heat and detoxifying have a better regulatory effect on kinases. By weakening the activity of kinases such as GSK-3 β, CDK5, JNK, ERK and regulating corresponding signaling pathways, the phosphorylation of corresponding sites of tau protein is inhibited, thereby slowing down the conversion of tau protein to phosphorylated tau protein. Although it is not yet possible to fully detect the phosphorylation sites of phosphorylated tau protein, differences in the effects of different kinases on tau protein phosphorylation can be demonstrated. In addition, the “Blood Syndrome Theory” states: “If there is blood stasis in the heart, it can also cause forgetfulness.” It is believed that blood stasis is one of the main pathogenic factors of AD. Experiments have shown that prescriptions with the effects of tonifying qi, promoting blood circulation, warming yang, and removing blood stasis have better therapeutic effects on AD, especially in regulating the excessive phosphorylation of tau protein; It can directly regulate phosphatase activity, enhance the dephosphorylation effect on phosphorylated tau protein, reduce the production of NFTs, and prevent and treat AD. In addition, the “Secret Records of the Stone Chamber” states: “Phlegm is the most abundant, and stagnation is the deepest.” During the Qing Dynasty, Chen Shiduo believed that “stagnation” was closely related to “phlegm.” Experiments have shown that formulas with the effects of tonifying the liver and kidneys, nourishing qi and yang, promoting blood circulation and removing blood stasis, and resolving phlegm and opening up orifices have a joint regulatory effect on kinases and phosphatases. Due to the strongest phosphorylation effect of GSK-3 β in kinases and the strongest dephosphorylation effect of PP2A in phosphatases, most studies focus on GSK-3 β and PP2A as the main detection targets to reveal the mechanism of traditional Chinese medicine’s multi pathway regulation of tau protein phosphorylation.

Traditional Chinese medicine can regulate the phosphorylation level of tau protein by affecting kinases, phosphatases, or both, achieving the goal of preventing and treating AD. As for the current research on traditional Chinese medicine, the author believes that there is still room for breakthrough in the following aspects: (1) Traditional Chinese medicine treatment has the characteristics of syndrome differentiation and treatment, which can be reflected in the process of disease differentiation in a large number of experiments, but the characteristics of syndrome differentiation have not been fully demonstrated. Therefore, the content of syndrome differentiation for experimental subjects can be added in animal experiments; (2) Traditional Chinese medicine and compound prescriptions have a definite therapeutic effect on AD, but due to their complex composition, the mechanism of action has not yet been elucidated, and their promotion credibility is low. Modern medical research technology can be further combined with traditional Chinese medicine for the prevention and treatment of AD. On the one hand, the effective ingredients of traditional Chinese medicine can be purified and analyzed, and on the other hand, the compatibility rules of traditional Chinese medicine for regulating kinases and phosphatases can be explored, attempting to explain the significance of drug compatibility at the molecular level; (3) Multiple types of kinases and phosphatases exhibit a network like interaction to regulate the phosphorylation level of tau protein. However, currently, in the same experiment, due to incomplete detection of the types of kinases and phosphatases and the phosphorylation sites of phosphorylated tau protein, it is not sufficient to construct a comprehensive understanding of the effects of traditional Chinese medicine on kinases and phosphatases. By increasing the types of detected kinases and phosphatases, as well as the phosphorylation sites of phosphorylated tau protein, more sufficient evidence can be found to demonstrate the network like regulatory system of traditional Chinese medicine on kinases and phosphatases; (4) Some studies only quantitatively analyze tau protein and phosphorylated tau protein, neglecting the detection of intermediate links (kinases, phosphatases, or other indicators), resulting in missing evidence chains and only displaying results without elaborating on the reasons. In subsequent research, intermediate evidence detection can be appropriately added to form a complete chain of evidence; (5) A large number of clinical and animal experiments have shown that traditional Chinese medicine has better therapeutic effects, but the toxic side effects of traditional Chinese medicine are not yet clear. It is recommended to increase toxicology experiments on related traditional Chinese medicine to provide safer guidance for its clinical use