Rheum undulatum Linné Exerts Neuroprotective Effects Against Aβ Oligomer-Induced Neuronal Damage by Modulating p53-Mediated Signaling.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Accumulating evidence indicates that β-amyloid oligomers (AβO), the most neurotoxic form of β-amyloid, play a critical role in the pathogenesis of AD by inducing synaptic loss, neuronal death, and neuroinflammation. Therefore, targeting AβO-driven pathological processes through multi-target therapeutic strategies represents a promising approach to treating AD. This study aimed to investigate the neuroprotective effects of Rheum undulatum Linné rhizome (RUL) and the underlying mechanisms of its action against AβO-induced neurotoxicity using integrated in vitro, in vivo, and in silico approaches. RUL treatment protected HT22 and N2a neuronal cells from AβO-induced neurotoxicity and reduced extracellular AβO levels. In AβO-injected mice, oral administration of RUL alleviated memory impairment, preserved synaptic integrity, as evidenced by increased PSD95 and SYP expression, and suppressed microglial and astrocytic activation, as indicated by reduced Iba-1 and GFAP immunoreactivity in the hippocampus. Mechanistically, systems-level network analysis identified p53-related signaling as a central regulatory axis in the AD-associated pathway. These network-level insights were experimentally validated by demonstrating that RUL suppressed p53 phosphorylation, increased the BCL2/Bax ratio, inhibited caspase-3 activation, and reduced pro-inflammatory cytokines, including TNF-α and IL-1β, in the hippocampus. Collectively, these findings demonstrate that RUL exerts neuroprotective effects by preserving synaptic integrity and concurrently suppressing apoptotic and neuroinflammatory pathways through the network-level modulation of AβO-driven pathology, supporting its potential as a multi-target therapeutic candidate for AD.