Alzheimer's disease (AD) is a serious degenerative disease of the central nervous system. The main pathological features are senile plaques formed from excessive deposition of β amyloid protein (Aβ) and Neurofibrillary tangles (NFTs) formed from abnormal phosphorylation of tau protein. The clinical manifestations are progressive memory loss and cognitive impairment (Jack, 2022). Due to the unclear pathogenesis, there are no effective therapeutic drugs at present. Clinically, the cholinesterase inhibitors (Donepezil, etc.) and NMDA receptor antagonists (Memantine) were often utilized to improve the cognitive function and alleviate the disease (Briggs et al., 2016). With the development of research, it has been found that neuroinflammation is closely involved in the pathological progression of AD. Aβ aggregates and p-tau proteins can activate microglia through pattern recognition receptors, and secrete a spectrum of inflammatory mediators and neurotoxic substances. Although, neuroinflammation served as double edged sword for the brain, it was suggested that persistent inflammation promoted the Aβ deposits and Tau phosphorylation, triggered neuron apoptosis and aggravated neurodegeneration (Dhapola et al., 2021).

Moreover, the specific immune response mediated by T cells is also closely involved in neuroinflammation. T cells are abnormally activated by autoantigens such as Aβ and p-tau proteins, thus triggering/exacerbating neuroinflammation (Machhi et al., 2020). Th1 and Th17 are the major effector T cell subsets that mediate neuroinflammatory responses. Adoptive transfer of Aβ-specific Th1 and Th17 cells could significantly promote microglial activation and neuroinflammation, and induce amyloid plaque deposition and memory impairment in APP/PS1 mice (Machhi et al., 2021). Regulatory T cells (Tregs) are another subgroup of T cells, which play an immunosuppressive role and maintain immune tolerance. Adoptive transfer of Aβ-specific Treg cells could attenuate neuroinflammation and improve memory and cognitive function in AD transgenic mice (Yang et al., 2022). Therefore, it might be a feasible strategy to treat or delay AD by modulating the function of T cells and alleviating the neuroinflammation.

Multiple researches indicated that T cell activation was accompanied with the increase in glycolytic metabolism, which was critical for satisfying the increased energetic and biosynthetic demands of activated cells. Also, glycolysis was engaged in the modulation of T cell differentiation process. For example, Inhibition of glycolysis could block Th17 cell differentiation and promote the generation of Treg cells in vitro (MacIver et al., 2013). The neuropeptide cortistatin weakens Th17 cell response and alleviates colitis via inhibiting glycolysis (Guo et al., 2022). Mechanistically, researches suggested that costimulation with anti-CD28 gave rise to the activation of PI3K/Akt/mTOR pathway, and subsequent Glut1 upregulation, which not only augmented the absorption of glucose in activated T cells, but also facilitated a switch from oxidative to glycolytic metabolism (Ganeshan and Chawla, 2014). Taken together, the modulation of glycolytic metabolism can affect the induction and outcome of immune responses as well as corresponding immunopathological processes.

Uncaria rhynchophylla (Miq.) Miq.ex Havil., also named as Gou-teng in China, is a classical medicinal plant belonging to Rubiaceae family, which has the properties of extinguishing wind, arresting convulsions, clearing heat and pacifying the liver, and is often used for the treatment of central nervous system-related diseases, such as hyperpyretic convulsion, headache and dizziness, epilepsy, and AD (Chinese Pharmacopoeia Commission, 2020; Yang et al., 2020). In many traditional compound preparations, U. rhynchophylla (UR) was used as a major component, such as chotosan (Gou-teng-san in Chinese) and yokukansan (Yi-gan-san in Chinese), both of which have been used for the treatment of AD and vascular dementia in clinic (Matsumoto et al., 2013). Up to now, the potential toxicity of UR on human remains unclear. The median lethal dose (LD50) of UR water extract is beyond 2 g/kg by oral administration in rats and mice. The LD50 of total alkaloids from UR is about 650 mg/kg by oral administration in mice (Yang et al., 2020). But, several studies had demonstrated that U. rhynchophylla possessed observable beneficial effects on AD which primarily arose from the presence of indole alkaloids via regulating the microglia-induced inflammation, inhibiting Aβ aggregation and neuronal toxicity, reducing acetylcholinesterase activity, alleviating glutamate excitotoxicity, enhancing the antioxidant capacity, and repairing synaptic dysfunction, etc (Ndagijimana et al., 2013; Yang et al., 2020). However, there are few reports on the regulation of URA on neuroinflammation mediated by CD4+ effector T (Teffs) cells.

In the present study, we systematically examined the therapeutic effects of URA on AD pathology in APP/PS1 mice, and investigated the involvement of CD4+ T cell in neuroinflammation. Then, we test the effects of URA on glycolysis and the involvement of PI3K/Akt/mTOR signaling pathway. This study will offer new insight into anti-AD mechanism of URA, and promote further development and application of UR in the treatment of AD. In addition, the chemical profile of URA was characterized and identified by UPLC-QTOF-MS/MS analysis.