Tenuifolin in the prevention of Alzheimer's disease‐like phenotypes: Investigation of the mechanisms from the perspectives of calpain system, ferroptosis, and apoptosis

Abstract

Polygala tenuifolia was documented to calm the mind and promote wisdom. However, its underlying mechanisms are still unclear. This study aimed to investigate the mechanisms underlying the effects of tenuifolin (Ten) on Alzheimer's disease (AD)‐like phenotypes. We first applied bioinformatics methods to screen the mechanisms of P. tenuifolia in the treatment of AD. Thereafter, the d‐galactose combined with Aβ1–42 (GCA) was applied to model AD‐like behaviors and investigate the action mechanisms of Ten, one active component of P. tenuifolia. The data showed that P. tenuifolia actioned through multi‐targets and multi‐pathways, including regulation of synaptic plasticity, apoptosis, and calcium signaling, and so forth. Furthermore, in vitro experiments demonstrated that Ten prevented intracellular calcium overload, abnormal calpain system, and down‐regulation of BDNF/TrkB signaling induced by GCA. Moreover, Ten suppressed oxidative stress and ferroptosis in HT‐22 cells induced by GCA. Calpeptin and ferroptosis inhibitor prevented the decrease of cell viability induced by GCA. Interestingly, calpeptin did not interrupt GCA‐induced ferroptosis in HT‐22 cells but blocked the apoptosis. Animal experiments further demonstrated that Ten prevented GCA‐induced memory impairment in mice and increased synaptic protein expression while reducing m‐calpain expression. Ten prevents AD‐like phenotypes through multiple signaling by inhibiting oxidative stress and ferroptosis, maintaining the stability of calpain system, and suppressing neuronal apoptosis.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

“…Fortunately, aducanumab has been approved for clinical use in the treatment of AD. As an alternative treatment of AD, traditional Chinese medicine has also demonstrated the potential to treat or prevent AD 4,5,14,16 . If, as mentioned in the above literature, OLs can also regulate Aβ, treatment strategies can be designed around OLs to suppress Aβ deposition.…”

“…A total of 211 studies were retrieved. Among them, 107 were excluded because they were either unrelated to this study (n = 14) or were informal published articles or review articles (n = 93).…”

“…Chinese medicine has also demonstrated the potential to treat or prevent AD. 4,5,14,16 If, as mentioned in the above literature, OLs can also regulate Aβ, treatment strategies can be designed around OLs to suppress Aβ deposition.…”

“…Classical neuropathological changes in AD, including the accumulation of amyloid plaque and the presence of neurofibrillary tangles, are responsible for neuronal loss and synaptic dysfunction, [13][14][15][16] but they may also induce death of OLs and myelin damage. 17,18 There is also evidence to show that myelin pathology may precede Aβ and tau pathologies in AD.…”

Saponin components in Polygala tenuifolia as potential candidate drugs for treating dementia

“…The tyrosine kinase receptor B (TrkB) serves as a receptor for BDNF, maintaining synaptic protein expression and neuronal survival ( Moya-Alvarado et al, 2023 ). Tenuifolin promotes neuronal cell survival and synaptic protein expression through the BDNF/TrkB signaling pathway ( Li et al, 2023 ). Aβ proteins can inhibit BDNF by reducing the expression of the cyclic AMP response element-binding protein (CREB), while CREB and BDNF-dependent increases promote dendritic growth in neuronal cell bodies.…”