Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.jep.2025.120508 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
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
August 2025
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,
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.
RABGAP1 is a sensor that facilitates the sorting and processing of amyloid precursor protein.
EMBO J
August 2025
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
A hallmark of Alzheimer's disease (AD) is the accumulation of extracellular amyloid-β plaques in the brain. Amyloid-β is a 40-42 amino acid peptide generated by proteolytic processing of amyloid precursor protein (APP) via membrane-bound proteases. APP is a transmembrane protein, and its trafficking to sites of proteolysis represents a rate-limiting step in AD progression.
View Article and Find Full Text PDFKey questions for the future of amyloid research in dementia: a framework for integrating complex datasets.
Mol Psychiatry
August 2025
Cambridge Public Health, University of Cambridge School of Clinical Medicine, Forvie Site, Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK.
Alzheimer's disease research is moving into a new era, yet significant questions remain about its underlying biological mechanisms. In this article, we consider how the field might refine the transfer of evidence between research cohorts focused on rare, genetically defined familial forms of dementia, clinical trial cohorts, highly selective of relatively younger people, with single neuropathologies and few co-morbidities, and the overall picture of the dementia syndrome in the whole population. We examine four key areas in which the evidence base must be improved: i) how 'disease' definitions apply across these three groups, ii) the precise molecular identification of the protein at the heart of current Alzheimer's research - amyloid beta protein, iii) the contributions of the full amyloid precursor protein proteolytic system and iv) how this complex proteolytic system relates to wider cellular systems.
View Article and Find Full Text PDFUnlabelled: The membrane-embedded γ-secretase complex is involved in the intramembrane cleavage of ∼ 150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38-43-residue secreted amyloid β-peptides (Aβ), with the aggregation-prone 42-residue form (Aβ42) particularly implicated in the pathogenesis of Alzheimer's Disease (AD). However, whether Aβ42 is the primary driver of neurodegeneration in AD remains unclear.
View Article and Find Full Text PDFPresenilin-1 Familial Alzheimer Mutations Impair γ-Secretase Cleavage of APP Through Stabilized Enzyme-Substrate Complex Formation.
Biomolecules
July 2025
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA.
Familial Alzheimer's disease (FAD) is caused by dominant missense mutations in amyloid precursor protein (APP) and presenilin-1 (PSEN1), the catalytic component of γ-secretase that generates amyloid β-peptides (Aβ) from the APP C-terminal fragment C99. While most FAD mutations increase the ratio of aggregation-prone Aβ42 relative to Aβ40, consistent with the amyloid hypothesis of Alzheimer pathogenesis, some mutations do not increase this ratio. The γ-secretase complex produces amyloid β-peptide (Aβ) through processive cleavage along two pathways: C99 → Aβ49 → Aβ46 → Aβ43 → Aβ40 and C99 → Aβ48 → Aβ45 → Aβ42 → Aβ38.
View Article and Find Full Text PDF