AD is the most common form of progressive dementia in the elderly, lines of evidence showed that stroke patient might be more likely to experience memory decline (Brainin, et al.,2015)as well as stroke could increase the risk of AD(Kuzma, et al.,2018). Here four TCMs examined in this research have well been reported in treating stroke patients clinically. D1 is produced from Erigeron breviscapus, a TCM in cold repelling, dehumidification, and pain relieving according to the theory of TCM. It remarkable effects on the improvement of neuron function damage of patients with acute cerebral infarction as well as drug combination therapy(Chao Zeng,2015). Vascular dementia patients who treated with D1 showed improving MMSE grading as well as blood dynamics of brain vessel(Wei-Jie Bai,2006); T2 is produced from Panax notoginseng and Cape Jasmine, the main gradients of which are Gin (a main gradient of PNS) and Gen. T2 improves the consciousness recovery and the cognitive function after ischemia stroke, especially show the remarkable effect in the memory repair of vascular dementia patients with cerebral infarction in 200 cases of double-blinded, multi-center comparison clinical trial (unpublished results). In vivo, T2 can improve spatial learning and memory in 10-month age of APP V717I Tg mice(Yang, et al.,2014); Q3 is produced from a variety of herbs, such as cholic acid, mother-of-pearl, hyodeoxycholic acid, medlar, buffalo horn, radix isatidis, baicalin, honeysuckle. It offers the neuroprotection effect in acute ischemia patient by inhibiting the adhesion of white blood cell and endothelia cell, relieving the damage of vascular endothelial cell as well as inhibiting the process of inflammation (Pengtao Li,2009;Lingming Sun,2016). In addition, Q3 injection can significantly improve the mental retardation degree, muscle strength and walking faculty of vascular dementia patients ; H4 is baicalin, extracted from the root of Scutellaria baicalensis Georgi. It attenuates cerebral ischemia via anti-oxidative and anti-apoptotic pathways (Cao, et al.,2011). Accompanied with jasminoidin and cholic acid, it further improved the cognitive function in ibotenic acid-induced rat models.
These TCMs are used in different aspects of stroke accompanied with different mechanisms in molecular levels. Then it is not surprise that their effect on APP pathway could be different: For D1, it increases Aβ level through accumulating more BACE1 protein and enzymatic activity inside the cell, but the ratio of Aβ42/Aβ40 decreases; for H4, it lowers BACE1 protein activity, as well as NEP, an important enzyme in Aβ clearance. These effects totally compensate and no different change occurred in Aβ production; Q3 reduces Aβ level by down-regulating BACE1 activity and expression; T2 shows the most active effect in reducing Aβ level and Aβ42/Aβ40 ratio in vitro, partially through down-regulating BACE1 level and activity. Further, it has been proved that Gin, rather than Gen plays a main role in BACE1 modulation. The mechanism of how Gin affects BACE1 protein level remains to be investigated. Since Gin was found to have an effect to stimulate glucose uptake (Li, et al.,2018;Zhou, et al.,2019), and glucose reduction, energy inhibition elevates BACE1 levels and activity and is potentially amyloidogenic in APP transgenic mice and it could possibly be the early events in AD pathogenesis (Velliquette, et al.,2005), suggesting the capability of enhance glucose uptake of Gin could be the key for its role in modulating BACE1 level and activity. In addition, it is worth to note that with a higher concentration, Gin shows effect on the modulation of γ-secretase expression. However, this effect is not shown when cells are treated with T2, therefore it might not or only partially account for the Aβ reduction in C99 transfected cell. This could be the effect of drug combination could be different from a single component’s.(Table 1)
The two major isolated gradients of T2, Gin and Gen have been reported to have multiple clinical effects, including anti-oxidation, anti-tumor, Type 2 diabetes etc. (http://en.wikipedia.org/wiki/Ginsenoside; http://en.wikipedia.org/wiki/Genipin). Gin are class of steroid-like compounds, a main gradient of Ginseng or Panax notoginseng saponin (PNS), the latter of which is extracted from Panax notoginseng, the component of T2 and a valuable herb widely used in TCM for stroke. PNS has the effect of inhibiting platelet aggregation, increasing the heart and cerebral blood flow and promotes angiogenesis in DG areas of hippocampus and plays a protective role in cardiovascular and cerebrovascular diseases (Yang, et al.,2014;Xu, et al.,2015;Tan,2020). A bench of clinical trials has been administrated for the treatment of PNS in hypertensive intracerebral hemorrhage and ischemic stroke (ClinicalTrials.gov identifier: NCT02999048, NCT01636154, NCT02544087). Ginseng was shown to have beneficial effects against amnesia induced by β-amyloid peptides in vivo (Wang, et al.,2006), Gin also have been shown to promote learning and memory capability, reduced Aβ level of AD mice (Chen, et al.,2006), as well as neuroprotective effect (Bao, et al.,2005), which is consistent to our study. GP is shown to inhibit microglia-mediated inflammatory responses, reduced the production of pro-inflammatory cytokines, decreased the cytotoxicity of Aβ and induced neurotrophic effects as well (Li, et al.,2014;Li, et al.,2012).
What’s more, it is well known that stroke results a hypoxic environment in the brain. Interestingly, Hypoxia was shown to facilitate AD pathogenesis by up-regulating BACE1 gene transcription; Hypoxia treatment markedly increased Aβ deposition and neuritic plaque formation and potentiated the memory deficit in Swedish mutant APP transgenic mice (Sun, et al.,2006); Our recent study also showed that the death of brain cells caused by a stroke or head injury may cause generation of Aβ by building up BACE1 protein level (Tesco, et al.,2007), raising the prospect that therapeutic intervention with such process could lower the risk of AD caused by stroke. What’s more, since in pathological aspect, stroke and AD both are very complicated and have multiple symptoms from blood vessel to neuron cell and multiple mechanism could be involved, the TCMs did not show effect on APP processing doesn’t mean they do not alleviate other symptoms of AD, such as H4. As a whole, anti-stroke TCMs show different mechanisms on APP processing, and have the potential to be used in AD treatment; particularly, T2 with its relatively simple components may be a promising candidate for the treatment of AD (Fig. 7).