AD is the most common form of dementia affecting the elderly . AD patients suffered progressive cognitive and functional deficits, which resulted in a heavy burden to patients, families, and the public health system . In 2019, AD affected more than 50 million people globally, which is expected to reach 152 million by 2050. In addition, the current annual cost of AD worldwide is $1 trillion, which is estimated to double by 2030 . Rising prevalence and mortality, and the lack of effective treatments, have resulted in huge costs to society. Currently, cholinesterase inhibitors (i.e., donepezil) and Nmethyl-D-aspartate (NMDA) receptor antagonists (i.e., memantine) are approved by FDA for the treatment of AD. However, these drugs can only moderately relieve symptoms and cannot really cure AD. Therefore, we need to find new treatment options to slow down the progression of AD.
Accumulation of Aβ is considered to be one of the main pathogenic features of AD, which causes a series of neuronal damage , leading to cognitive dysfunction . Aβ plaques affect synaptic morphology and function by disrupting the synaptic signaling pathway, leading to memory loss and behavioral changes . Moreover, Aβ oligomers deposited extracellular can also activate microglia and subsequently release inflammatory cytokines, the amount of APP will increase due to the large release of these factors. As the amount of APP increases, the production of Aβ becomes higher [6, 7]. Severe oxidative stress and neuroinflammation, loss of synaptic connections in specific brain regions, cumulative emergence of intracellular tau pathology, and accumulation of extracellular amyloid Aβ plaques form a complex neurodegeneration [8, 9]. Therefore, we believe that it is difficult to cure the complex disease with multiple pathological factors by single target chemical drugs. CG (Tianjin Tasly Pharmaceutical Co., Ltd, Tianjin, China) was approved by the National Medical Products Administration (NMPA) in 1996 for treatment of headache and dizziness associated with cerebrovascular diseases. It is consists of 11 herbs, including Angelicae Sinensis Radix, Paeoniae Radix Alba, Chuanxiong Rhizoma, Rehmanniae Radix Praeparata, Uncariae Ramulus Cum Uncis, Spatholobi Caulis, Corydalis Rhizoma, Prunellae Spica, Margarita, Cassiae Semen, and Asari Radix et Rhizoma. These 11 herbs contain a large number of chemical components. Some of these ingredients are key to the treatment of diseases in traditional Chinese medicine and are the main sources of new drug lead compounds . For example, paeoniflorin, albiflorin, rosmarinic acid, chlorogenic acid, tetrahydropalmatine, caffeic acid, gallic acid, and ferulic acid (Fig. 1c) are known to improve learning and memory deficits, attenuate neurotoxicity, and anti-oxidant damage [11–15]. Previous studies have shown that the ingredients mentioned above can be detected in blood of mice after oral administration of CG [16, 17]. Due to the complicated mechanisms of TCM, these ingredients were usually used as part of a combination therapy rather than monotherapy . Studies have shown that as a supplementary treatment of modern medicine, TCM improved the therapeutic effect of modern medicine. For example, after intraperitoneal injection of pentobarbital sodium, rats were given He jie Zhitong prescription by gavage, the sleep latency of rats was significantly decreased, and the sleep time was prolonged, suggesting that Hejie Zhitong prescription exerted a synergistic effect with pentobarbital sodium . Shufeng Jiedu Capsule enhanced doxorubicin therapeutic efficacy in hepatocellular carcinoma by inhibiting migration and invasion . Fuzheng Kang Ai decoction combined with erlotinib enhances the effect of lung cancer treatment . Xiaoaiping injection enhanced paclitaxel efficacy in ovarian cancer proliferation by inhibiting pregnane X receptor . Huyang Yangkun Formula could enhance the therapeutic effect of embryonic stem cells on premature ovarian failure mice. This combined therapy could promote the development of mice follicles and inhibit the expression of the TGF-β1/TAK1 pathway . These results suggest that the combination therapy of TCM and western medicine is feasible in the treatment of various diseases. However, there were no studies on attenuation Alzheimer-like pathology of combination therapy of CG and other chemotherapy drugs.
Mm is a moderate-affinity, uncompetitive NMDA receptor antagonist. It is used to improve cognitive and behavioral disorders in moderate to severe AD patients [24, 25]. To illustrate whether CG can enhance the therapeutic effect of Mm on AD, and explain the potential synergies, the APP/PS1 mice model was used to solve the puzzle. As a result, the combination of CG and Mm had a stronger anti-AD effect than the single treatment. Meanwhile, the expressions of PSD95, SYN, GAP43, APP, APPβ, APPα, and BACE1 have correspondingly changed, which may be the reason for the synergistic anti-Alzheimer's efficacy.
Our work provides a comprehensive explanation for the synergistic effect of CG combined with Mm against Alzheimer's disease in terms of anti-inflammatory, anti-oxidant damage, reducing Aβ deposition and maintaining synaptic connections, providing a new idea combination therapy of Alzheimer's disease for the combination treatment of Chinese medicine and Chemical drugs.