Single-nucleus RNA sequencing and network pharmacology reveal the mediation of fisetin on neuroinflammation in Alzheimer's disease

Abstract

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive function and memory. This study explores cellular subgroups in AD using single-nucleus RNA sequencing (snRNA-seq). It integrates the pharmacological network of traditional Chinese medicine (TCM) to identify potential therapeutic targets, providing a theoretical basis for the development of clinical AD.

Methods: We obtained data information from the Gene Expression Omnibus (GEO) for snRNA-seq analysis. Enrichment and pseudotime analysis were performed to explore the functions and differentiation pathways of cellular subgroups. Cellular communication networks were mapped to reveal subgroup interactions. Additionally, a pharmacological network for AD was constructed using the TCM pharmacology database.

Results: We identified several cell subgroups associated with AD pathology, contributing to disease progression in various ways. Notably, the TNC⁺ CD44⁺ astrocyte subgroup activated the I-kappa B kinase/ NF-κB signaling pathway, leading to increased expression of inflammatory cytokines. In the pharmacological network, fisetin was identified as a promising compound with the potential to bind to the CD44 protein, mitigating the inflammatory response and preventing further neuronal damage.

Conclusions: By exploring the ecological landscape of various cellular subgroups in AD and investigating the roles and mechanisms, combined with molecular docking and pharmacological network screening, our findings provide new insights and therapeutic possibilities for AD treatment.

Keywords: Alzheimer's Disease; CD44; Fisetin; TNC; Traditional Chinese medicine; snRNA-seq.