Alzheimer's disease (AD), a common neurodegenerative disease, is characterized by a progressive decline in both cognitive ability and impaired memory, as well as changes in personality and behavior. The total number of AD patients is predicted to reach 82 million by 2030 and 152 million by 2050 (Jia et al., 2018). The pathogenesis and etiology of AD are not yet fully elucidated, and donepezil and other cholinesterase inhibitors are administered primarily for clinical treatment (Haake et al., 2020). Still, these drugs relieve symptoms for only a short period and do not postpone AD's advancement. Recent failures and limited therapeutic drug advances in phase III clinical trials suggest that it is time to consider alternative strategies for AD treatment (Qian et al., 2015).

Interestingly, Previous studies have found that the administration of 20 IU or 40 IU of insulin (INS) in 104 participants for 120 days demonstrated that two dosages improve performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) (Craft et al., 2012). Investigation in animals has revealed that insulin facilitated modifications in hippocampal synaptic plasticity (Moult and Harvey, 2008). In AD cases, brain insulin resistance thus appears to be an early and common feature and the insulin signaling pathway is significantly impaired (Talbot et al., 2012). Expression of insulin receptor (IR), Insulin Receptor Substrate-1(IRS-1), Phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), glycogen synthase kinase 3β (GSK3β), and Glucose Transporter 4 (GLUT4) have been associated with insulin resistance (Carnagarin et al., 2015). The association between the PI3K/AKT signaling pathway and the metabolism of Aβ oligomers and hyper-phosphorylated Tau protein has been studied previously (Ren et al., 2019; Razani et al., 2021). Recently, the PI3K/AKT signaling pathway has been characterized as a critical intermediate in the central nervous system (Matsuda et al., 2019), and many natural ligands based on the PI3K/AKT signaling pathway have been detected to protect neurons and inhibit microglia activation, thus contributing to the prevention and treatment of AD (Long et al., 2021).

The dry ripe sarcocarp of Cornus officinalis, a herb and food plant used in traditional Chinese medicine (TCM) (Liu et al., 2011), contains an abundance of terpenoids such as flavonoids, tannins, polysaccharides, phenylpropanoids, sterols, carboxylic acids, furans, and mineral substance (Czerwińska and Melzig, 2018). Cornus officinalis extract possesses a variety of biological activities such as anti-inflammatory, antioxidant, anti-apoptotic, anti-diabetic, neuroprotective, and cardiovascular protective activities (Gao et al., 2021). Cornus officinalis has been utilized since ancient times to treat diabetes mellitus (DM). In contemporary times, several chemicals in Cornus officinalis have revealed the capability to inhibit Aβ1-42-induced apoptosis and inflammation, Tau hyperphosphorylation, and Tau aggregation (Ma et al., 2019; Chen et al., 2018; Bhakta et al., 2017). Based on the TCM database, THA in Cornus officinalis is filtered. THA, a selective alpha 2-adrenoceptor antagonist can protect against ischemic neuronal injury via autophagy regulation (Roquebert and Demichel, 1984; Liao et al., 2023). However, there are no experiments to screen for THA in Cornus officinalis that can protect neurons through PI3K/AKT signaling pathway.

In this study, we employed a systematic study of multi-scale mechanisms, which combined transcriptomic analysis, drug prediction, network pharmacology, and molecular docking, to investigate the therapeutic effects of Cornus officinalis on AD and to screen for THA from Cornus officinalis that may have therapeutic effects on core AD targets (Hopkins, 2008; Xie et al., 2022). Subsequently, experiments were designed to identify the potential mechanism of THA on the core target (Fig. 1). This study will provide important implications for the treatment of AD.