Molecular mechanisms of sulforaphane in Alzheimer's disease: insights from an in-silico study

Abstract

This study was to identify the molecular pathways that may explain sulforaphane's Alzheimer's disease (AD) benefits using multiple advanced in silico approaches. We found that sulforaphane regulates 45 targets, including TNF, INS, and BCL2. Therefore, it may help treat AD by reducing neuroinflammation, insulin resistance, and apoptosis. The important relationships were co-expression and pathways. 45 targets were linked to the midbrain, metabolite interconversion enzymes, 14q23.3 and 1q31.1 chromosomes, and modified residues. "Amyloid precursor protein catabolic process", "regulation of apoptotic signaling pathway", and "positive regulation of nitric oxide biosynthetic process" were the main pathways, while NFKB1, SP1, RELA, hsa-miR-17-5p, hsa-miR-16-5p, and hsa-miR-26b-5p were transcription factors and miRNAs implicated in sulforaphane In AD treatment, miRNA sponges, dexibuprofen, and sulforaphane may be effective. Furthermore, its unique physicochemical, pharmacokinetic, and biological qualities make sulforaphane an effective AD treatment, including efficient gastrointestinal absorption, drug-like properties, absence of CYP450 enzyme inhibition, not being a substrate for P-glycoprotein, ability to cross the blood-brain barrier, glutathione S-transferase substrate, immunostimulant effects, and antagonistic neurotransmitter effects. Sulforaphane is a promising compound for AD management. Further work is needed to elucidate its therapeutic effects based on our findings, including genes, miRNAs, molecular pathways, and transcription factors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00267-4.

Keywords: Alzheimer’s disease; In silico; Molecular mechanisms; Post-translational modification; Sulforaphane.

Fig. 1

Detailed workflow for identifying and analyzing sulforaphane-related targets in Alzheimer’s disease

Fig. 2

Network interaction and post-translational modifications of targets involved in AD pathogenesis regulated by sulforaphane. A Network interaction of the 45 sulforaphane-regulated targets, primarily characterized by co-expression (30.2%) and pathway interactions (25.4%), visualized using GeneMANIA (https://genemania.org). B Chromosomal locations of these targets, with 14q23.3 and 1q31.1 exhibiting the highest distribution ratios. C Functional classification of the targets, highlighting metabolite interconversion enzymes (17%), transporters (10%), intercellular signaling molecules (10%), and gene-specific transcriptional regulators (10%) based on Panther classification (http://www.pantherdb.org/). D Identification of hub targets (TNF, INS, and BCL2) through network topology analysis, utilizing degree, betweenness, and closeness scores. E Post-translational modifications (PTMs) of hub targets visualized using Uniprot (https://www.uniprot.org), with key modifications including modified residues (32%), chains (26%), and disulfide bonds (21%)

Fig. 3

Direct interactions between sulforaphane and key targets involved in AD. A Sulforaphane’s interaction with TNF, illustrating its potential role in neuroinflammation. B Interaction with INS, suggesting implications for insulin signaling in cognitive function. C Interaction with BCL2, highlighting its relevance in apoptosis regulation. Each panel presents structural details to elucidate the binding mechanisms

Fig. 4

Molecular dynamics simulation of sulforaphane binding to tumor necrosis factor (TNF) associated with AD. A Root mean square deviation (RMSD) showing stability over time. B Root mean square fluctuation (RMSF) analysis of amino acid variations during the simulation. C Count of hydrogen bonds formed between sulforaphane and TNF, indicating binding strength. D Radius of gyration assessing the compactness of the TNF structure. E Solvent-accessible surface area (SASA) illustrating conformational stability of the sulforaphane-TNF complex throughout the simulation

Fig. 5

Biological processes, molecular functions, pathways, and protein–protein interactions (PPI) targeted by sulforaphane in AD. A Overview of key biological processes affected by sulforaphane, highlighting mechanisms related to nitric oxide synthesis and apoptosis regulation. B Molecular functions of the targets, indicating roles in enzymatic activity and signaling. C Key signaling pathways impacted by sulforaphane, relevant to AD pathogenesis. D PPI analysis revealing the interaction landscape among targets, performed using Cytoscape ClueGO and Metascape

Fig. 6

miRNA-target interactions relevant to AD and influenced by sulforaphane. A miRNA-target network depicting significant regulatory relationships among identified miRNAs and their target genes. B Signaling pathways associated with these interactions, highlighting their roles in AD pathology. C List of diseases linked to the identified miRNAs, demonstrating their broader relevance in neurodegeneration, analyzed using MIENTURNET

Fig. 7

Biological activities of sulforaphane contributing to its protective effects against AD. This figure summarizes the pharmacological activities of sulforaphane, including its roles as an antioxidant, immunostimulant, and potential neuroprotective agent. Each biological activity is quantified, providing insights into how sulforaphane may ameliorate AD pathology, evaluated using PassOnline