Alzheimer’s disease (AD) is a multifactorial, age-related neurodegenerative disease, and currently available clinical drugs have limited efficacy. Existing cell models for anti-AD drug screening are mostly based on single-gene transfection and thus cannot fully reproduce the complex pathological features of AD. Although transgenic animal models can better mimic AD pathology, they are time-consuming, costly, and subject to high individual variability. Therefore, more efficient and reliable in vitro screening models are urgently needed.
This research is led by Professor Haiyu Zhao and Xiaolu Wei (State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China), aiming to construct a novel AD cell model and establish an anti-AD drug discovery strategy.The team constructed a U251MG cell line stably expressing the APP695/PS1-ΔE9 double transgenes via lentiviral transfection and named this cell line AD12. Using this LPS-AD12 cell model, multiple TCM-derived alkaloids were screened, and benzoylaconitine (BAC) was identified as the most effective anti-AD candidate compound through molecular docking and transmission electron microscopy analysis. Targeted metabolomics analysis indicated that the pharmacological activity of BAC was mainly associated with its anti-inflammatory effects, modulation of the cholinergic signaling pathway, and regulation of energy metabolism, and that BAC significantly reduced Aβ 1−42 and IL-6 levels. On this basis, the therapeutic effect of total alkaloids of Aconite (AE) was further validated in a 5xFAD mouse model, and the results demonstrated that AE has significant anti-AD potential.
This study established a strategy encompassing "cell model development → monomer evaluation → effective component group identification for drug discovery". This screening system is expected to accelerate the screening and discovery of anti-AD drugs and provide a feasible framework for subsequent in-depth research on new drug development based on TCM, thereby promoting the modernization of TCM-derived therapeutics.
See the article:
A progressive discovery strategy for anti-Alzheimer ’ s drug identification: In vitro screening with an LPS-induced neuroinflammatory cell model and in vivo validation in 5xFAD mice
https://www.ovid.com/jnls/stcm/fulltext/10.1097/st9.0000000000000100
Science of Traditional Chinese Medicine
A progressive discovery strategy for anti-Alzheimer’s drug identification: In vitro screening with an LPS-induced neuroinflammatory cell model and in vivo validation in 5xFAD mice
18-Sep-2026