Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive dysfunction (Scheltens et al., 2021; Cappai, 2016). Alzheimer's Disease International estimates that around 50 million people worldwide suffered from dementia in 2018, a number that is expected to triple by 2050 (Alzheimer’s Disease International (ADI), 2018). AD is characterized by hyperphosphorylated neurofibrillary tangles and beta-amyloid (Aβ) plaque deposits, which are crucial to AD pathophysiology (Breijyeh and Karaman, 2020; Pastorino and Lu, 2006). Aβ is generated from the amyloid precursor protein (APP) following two cleavages (Tiwari et al., 2019). Complex relationships exist between Aβ and autophagy (Kuang et al., 2020). Autophagy degrades Aβ and reduces the accumulation of Aβ in the hippocampus (Boland et al., 2008). Nevertheless, APP and presenilin-1 within autophagosomes facilitate Aβ production (Yu et al., 2005). Scholars widely contend that aberrant autophagy processes may exacerbate AD (Spilman et al., 2010; Caccamo et al., 2010). Besides heredity, the progression of AD is associated with various other risk factors, including obesity, hypertension, and depression (Livingston et al., 2020). Recent investigations into the mechanism of AD propose that the cis-phosphorylated tau protein following cerebral ischemia might serve as a potential mechanism underlying its spread from one neuron to another (Pluta and Czuczwar, 2024). Aberrant protein folding occurs, subsequently resulting in extensive neuronal death and impairment of the neuronal network and this cascade of events ultimately triggers AD (Pluta, 2024). The accumulation of amyloid plaques and the formation of neurofibrillary tangles further exacerbate oxidative stress within brain cells (Pluta et al., 2022). The etiology of AD is intricate, the exact mechanism remains unclear, and the efficacy of existing therapy agents is restricted (Elmaleh et al., 2019). To improve the quality of life of AD patients and reduce the burden on their families and society, it is essential to understand the pathogenesis of AD and the therapeutic targets of drugs.

Ginseng is a traditional Chinese herbal medicine. The roots and stems of ginseng have historically been utilized as medicine in many Asian countries (Xie et al., 2018). Ginsenosides are the main pharmacological components of ginseng roots (Liu et al., 2019). There are mainly two types of ginsenosides, protopanaxadiol (PPD) and protopanaxatriol (PPT), based on their different chemical structures (Zheng et al., 2018). Ginsenoside Rg1 is a PPT ginsenoside and one of its most significant pharmacologically active constituents (Xie et al., 2015). Ginsenosides have been confirmed to exhibit antioxidant (Xiong et al., 2019), anti-apoptotic (Zhou et al., 2019), and neuroprotective properties (Ahmed et al., 2016). Ginsenosides exert a protective effect in neurological disorders, including Parkinson's disease (Song et al., 2017), cerebral ischemia-reperfusion injury (Liu et al., 2019), and AD (Yang et al., 2022; Quan et al., 2013). Rg1 has the most effective effect on memory function repair in AD models (Sheng et al., 2015). Ginsenoside Rg1 has been employed for the therapy of amnesia, a prominent characteristic of AD (Jiao-Jiao et al., 2022). Liang et al. performed several cognitive-behavioral tests, and the meta-analysis results indicated that ginsenoside Rg1 markedly enhanced cognitive behavioral dysfunction in different AD models (Liang et al., 2021). Potential mechanisms include antioxidant activity, synaptic protection, and neuroprotection by modulating several signaling pathways (Liang et al., 2021). However, the precise target of Rg1 and its anti-AD mechanism remains ambiguous, hindering the advancement of Rg1 and ginseng-related pharmaceuticals.

FGR, officially designated as FGR proto-oncogene and referred to as SRC2, is a member of the Src family of non-receptor tyrosine kinases (Alliance of Genome Resources, 2024). The study conducted by Qiu demonstrated that patients with AD expressed greater levels of FGR in their blood (Qiu and Weng, 2022). Besides tubulin, tau protein binds to a variety of other proteins, such as the SH3 domain of Src family tyrosine kinases (Hugh Reynolds et al., 2008). Nonetheless, the involvement of FGR in the AD process has not been reported. Sirtuin 1 (SIRT1), a member of the nicotinamide adenine dinucleotide (NAD+)-dependent enzyme family, is crucial for controlling the autophagy process via its deacetylase activity (Yi et al., 2012; Ogura et al., 2016). SIRT1 is predominantly detected in regions implicated in neurodegenerative processes, including the prefrontal cortex, hippocampus, basal ganglia, cerebellum, and hypothalamus (Rizzi and Roriz-Cruz, 2018). FGR has been reported to bind to SIRT1 (Liu et al., 2023), resulting in reduced expression of SIRT1, which subsequently impairs autophagic flux (Bai et al., 2021). It remains unclear whether FGR plays a role in autophagy dysfunction of AD.

In this study, we used Aβ1–42 to challenge AD mice and HT22 cells to establish an AD model and explored the specific mechanism of Rg1 alleviating AD through overexpression or knockdown of FGR in vivo and in vitro. Our results provide valuable information for understanding the molecular mechanisms underlying FGR-mediated Rg1 mitigation effect in AD.