Abstract

   Alzheimer’s disease (AD) is a common and serious neurodegenerative
   disease in the elderly; however, the treatment of AD is still lacking
   of rational drugs. In this paper, the active constituents and targets
   of the self-developed Chinese medicine Formula 9002A in the treatment
   of AD were investigated from three aspects: pharmacodynamics based on
   cell and animal experiments, network pharmacology analysis, and
   pharmacokinetic analysis. A total of 124 compounds were screened in
   Formula 9002A, and four constituents including salidroside, gastrodin,
   niacinamide, and umbelliferone were screened as potential active
   components for the treatment of AD by network pharmacology. Among them,
   salidroside and gastrodin showed higher relevance with AD targets, such
   as ESR1 and AR. The pharmacokinetic study showed that they could be
   absorbed and identified in plasma; the half-life and mean residence
   times of salidroside and gastrodin in plasma were nearly increased
   2-fold by the administration of Formula 9002A compared with those by
   the administration of a monomer, indicating the extended action time of
   active compounds in vivo. Formula 9002A exerted the efficacy in the
   treatment of AD mainly by regulating APP, GSK3β, ESR1, and AR targets
   based on the anti-β-amyloid protein deposition, anti-oxidation and
   anti-apoptosis pathways. Two genes enriched in Alzheimer’s disease
   pathway, APP and GSK3β, were further validated. The experiments also
   demonstrated that Formula 9002A could downregulate APP and GSK3β
   protein expression in the model mice brain and improved their cognitive
   ability. In summary, Formula 9002A has the characteristics of multiple
   targets and multiple pathways in the treatment of AD, and salidroside
   and gastrodin might be the main active constituents, which could
   provide a foundation for further research and application.

   Keywords: Chinese medicine formula 9002A, Alzheimer’s disease,
   UPLC-MS/MS, salidroside, network pharmacology

1 Introduction

   COVID-19 is sweeping the world, and many countries are still at risk
   now. Quarantine measures are considered effective anti-epidemic
   measures. However, the social isolation of the elderly is considered a
   “serious public health problem” because they are at the higher risk of
   cardiovascular disease, autoimmune, neurocognitive, and mental health
   problems ([48]Armitage and Nellums, 2020). A total of 4,226 case
   reports in the United States showed that more than 80% of deaths in
   adult patients occurred over the age of 65 ([49]Shahid et al., 2020).
   Alzheimer’s disease (AD) is a very common and burdensome
   neurodegenerative disease in the elderly. Its prevalence and mortality
   rate are increasing much faster than previous researchers have
   expected. Between 2000 and 2018, the death toll increased by 146.2%.
   From the national financial perspective, the total cost of medical,
   long-term care, and hospice services for dementia patients are
   detrimental to the development of the country. In addition, Alzheimer’s
   patients have a higher risk of contracting COVID-19, which is supported
   by data ([50]Mok et al., 2020), and some studies have explained it from
   the genetic level ([51]Kuo et al., 2020). ApoE e4e4 is a gene known to
   be associated with AD, which not only affects lipoprotein function and
   subsequent cardiovascular disease but also reduces the
   pro-inflammatory/anti-inflammatory phenotype of macrophages, which
   results in the higher risk of severe COVID-19 ([52]Tudorache et al.,
   2017). These data demonstrated that much more attention should be paid
   to the basic health problems of the elderly after the outbreak of
   COVID-19.

   Traditional Chinese Medicine (TCM), a time-honored discipline, has
   performed well in the prevention and treatment of COVID-19. In fact,
   the treatment of neurodegenerative diseases of TCM is also widely and
   historically documented. A 22-year study on the benefits of taking the
   extracts of Ginkgo biloba L. on the long-term risk of dementia and
   death in the elderly showed that patients who were given Ginkgo biloba
   L. had a lower mortality rate ([53]Dartigues et al., 2017). Similar
   results were observed in the study on the effects of Ginkgo biloba L.
   on AD symptoms; patients taking Ginkgo biloba L. showed significant
   improvement ([54]Savaskan et al., 2018). Our laboratory jointly
   developed a Chinese Medicine Formula 9002A with many Chinese medicine
   experts based on their clinic experiences and some references. The