2. Academic Validation
  3. Ferulic acid derived from Huanshaodan improves cognitive deficits in Alzheimer's disease model through regulating APP proteolytic processing via downregulation of SIRT2 expression

Ferulic acid derived from Huanshaodan improves cognitive deficits in Alzheimer's disease model through regulating APP proteolytic processing via downregulation of SIRT2 expression

  • J Ethnopharmacol. 2025 Aug 29:354:120508. doi: 10.1016/j.jep.2025.120508.
Yunfang Su 1,  Congcong Shang 1,  Bing Cao 1,  Huifen Ma 1,  Pan Wang 1,  Junying Song 1,  Zhishen Xie 1,  Zhenqiang Zhang 2
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Collaborative Innovation Center of Prevention and Treatment of Major Diseases By Chinese and Western Medicine, Henan Province, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
  • 2 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Collaborative Innovation Center of Prevention and Treatment of Major Diseases By Chinese and Western Medicine, Henan Province, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China. Electronic address: zhang_zhenqiang@126.com.
PMID: 40886864 DOI: 10.1016/j.jep.2025.120508
Abstract

Ethnopharmacological relevance: Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents and mechanistic basis remain poorly understood.

Aim of the study: To identify the components derived from HSD that inhibit SIRT2 and investigate the underlying mechanisms in mitigating AD pathogenesis.

Materials and methods: A luciferase reporter gene assay was employed to screen HSD for components that downregulate SIRT2 expression. The neuroprotective effects and the mechanisms of the screened component, ferulic acid (FA), was evaluated both in SAMP8 mice and HT22-APPswe cell using behavioral tests, H&E, immunohistochemistry, transmission electron microscopy, ELISA, MTT, Western blot, RT-qPCR, immunofluorescence and Co-immunoprecipitation, to assess its effect on SIRT2 expression, SIRT2-APP interaction, as well as the expression of proteins associated with APP proteolytic processing. SIRT2-overexpressing plasmids were transfected to assess FA's neuroprotection via SIRT2 modulation.

Results: As a component in HSD, FA inhibited SIRT2 promoter-driven transcription, ameliorated cognitive deficits, protected neuronal and synaptic structures, reduced Aβ deposition in SAMP8 mice and Aβ level in HT22-APPswe cells. FA suppressed SIRT2 expression, inhibited SIRT2-APP interaction, modulated the expression levels of proteins involved in APP proteolytic processing, namely ADAM10, sAPPα, BACE1, sAPPβ, and CTFα in vitro and in vivo. Notably, the regulatory effects of FA on APP proteolytic processing in HT22-APPswe cells were completely abolished upon SIRT2 overexpression.

Conclusions: This study demonstrates that FA is an active component in HSD that mitigates AD pathology, potentially by modulating APP proteolytic processing through SIRT2 downregulation.

Keywords

APP proteolytic processing; Alzheimer's disease; Ferulic acid; Huanshaodan; SIRT2.

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