Dendrobium nobile alkaloids modulate calcium dysregulation and neuroinflammation in Alzheimer's disease: A bioinformatic analysis

Dendrobium nobile Lindl alkaloids, or DNLA for short, are the most active ingredients found in D.nobile, a top grade plant in Shen Nong Ben Cao Jing, with an extensive history of medicinal use in Chinese traditional medicine (TCM) as a multifunctional therapeutic agent. Recent evidence has emerged linking the neuroprotective and anti-aging effects of DNLA to their involvement in promoting autophagy of toxic amyloid-β (Aβ) plaques and modulation of key enzymes involved in the hyperphosphorylation of Tau proteins. Although amyloid buildup and the aggregation of Tau proteins are central to the onset of Alzheimer's disease (AD), evidence on how DNLA relate to other overlooked dysregulated AD-associated pathways is still lacking. We intend on deciphering the underlying mechanisms driving the anti-AD effect of DNLA, using a combination of network analysis based on differentially expressed genes found in AD patients, target fishing, centrality analysis, enrichment analysis and hub genes identification. In total, 2069 genes were found differentially expressed in SRP181886 and a PPI network constructed with common targets between DNLA and AD. Five hub genes were identified having a discriminatory power greater than 0.7; HTR2A, GRIN2B, GABRA1, HTR2C, GRIN2A, with the former being the top bottleneck node in the network. Enrichment analysis found that DNLA exert an anti-AD effect through the regulation of the calcium signaling pathway and the serotonergic system, by modulating key receptors implicated in excitatory/inhibitory neurotransmission. Additionally, DNLA were found to modulate two subunits of NMDA receptor involved in the release of pro-inflammatory cytokines, underlying the possible involvement of DNLA in neuroinflammation. This further emphasizes the therapeutic value of D.nobile and the multi-target, multi-pathway potential of DNLA to counteract the deleterious effects of calcium dysregulation and excitatory toxicity in AD, while providing evidence-based rationale behind the traditional use of D. nobile in TCM.