Ganoderic Acid A To Alleviate Neuroinflammation of Alzheimer’s Disease in Mice by Regulating the Imbalance of the Th17/Tregs Axis

Abstract

Ganoderic acid A (GAA) is a kind of lanostane-type triterpenoid isolated from Ganoderma lucidum. Imbalance of the Th17/Tregs axis exists in the progress of neuroinflammation of Alzheimer's disease (AD). In this study, the alleviating neuroinflammatory effect of GAA on D-galactose mice was studied from the aspect of regulating the imbalance of the Th17/Tregs axis. The Morris water maze test was used to evaluate the cognitive ability of AD mice. Flow cytometry was used to detect the percentages of IL-17A, IL-17F, IL-21, IL-22, and CD4 + CD25 + Foxp3 + in peripheral blood. Transmission electron microscopy was used to assess the cerebral mitochondrial ultrastructure. Metabolomic analysis based on gas chromatography−mass spectrometry was used to evaluate the mitochondrial dysfunction metabolism. Western blot analysis was used to detect the protein expressions of cytokines secreted by Th17 cells and Treg cells in the brain. As the results show, GAA has an alleviating neuroinflammatory effect on AD mice via regulating the imbalance of the Th17/Tregs axis. The potential mechanism was related to inhibition of the JAK/STAT signaling pathway induced by Th17 cells and enhancement of the mitochondrial oxidative phosphorylation by regulating Treg cells, thereby improving mitochondrial dysfunction of AD mice.

Identification of potential neuroprotective compound from Ganoderma lucidum extract targeting microtubule affinity regulation kinase 4 involved in Alzheimer's disease through molecular dynamics simulation and MMGBSA

“…Ganoderic acid A reduces Aβ42 levels in microglia cells by enhancing autophagy via the Axl/Pak1 signaling pathway. Ganoderic acid A ameliorates cognitive deficiency in the AD mouse model and even reduces Aβ42 in mouse 30 . Yue et al (2021) showed that ganoderic acid A attenuates LPS‐induced neuroinflammation in BV2 microglia by activating the farnesoid X receptor (FXR) 31 .…”

Ganoderma Lucidum Triterpenoids Improve Maternal Separation-Induced Anxiety- and Depression-like Behaviors in Mice by Mitigating Inflammation in the Periphery and Brain

“…Triterpenes are one of the main and important active ingredients of G. lucidum , which can inhibit inflammatory responses, including peripheral [ 60 ] and brain inflammation. Previous studies show that ganoderic acid A ameliorates LPS-induced neuroinflammation by activating the farnesoid x receptor in vitro [ 61 ] and balances the Th17/Tregs axis to attenuate the neuroinflammation of Alzheimer’s disease in mice [ 23 ]. Deacetyl ganoderic acid F, another kind of triterpene obtained from G. lucidum , was found to suppress LPS-induced neural inflammation in vivo and significantly reduce the expression of inflammatory factors in the peripheral serum of mice [ 25 ].…”

“…As a category of the main bioactive and medicative components in G. lucidum , Ganoderma lucidum triterpenoids (GLTs) are documented to perform various pharmacological actions such as anticancer [ 11 ], anti-inflammation [ 12 , 13 ], anti-atherosclerosis [ 14 ], anti-hyperlipidemia [ 15 ], antioxidants [ 16 , 17 ], antivirus [ 18 ], hepatoprotection [ 19 ], retardation renal cyst [ 20 ], renal fibrosis development, and protection of renal ischemia-reperfusion injury [ 21 ]. Moreover, recent studies evidence that GLTs can also exert pharmacological effects on the nervous system, alleviating neuronal apoptosis [ 22 ] and neuroinflammation [ 23 ] in Alzheimer’s disease mice. As components of GLTs, ganoderic acid [ 24 ] and deacetyl ganoderic acid F [ 25 ] were found respectively to improve 5-fluorouracil-induced cognitive dysfunction and inhibit lipopolysaccharide (LPS)-induced neural inflammation.…”

The role of Th17 cells/IL-17A in AD, PD, ALS and the strategic therapy targeting on IL-17A

“…Some compounds from plants could reduce the associated neuroinflammation in AD. For example, acid alpha-glucosidase (GAA), a kind of lanostane-type triterpenoid isolated from Ganoderma lucidum, was found to have an alleviating neuroinflammatory effect on AD mice via regulating the imbalance of the Th17/Tregs axis [ 96 ]. OMT, an alkaloid component extracted from the root of Sophora flavescens Ait, could reduce the level of pro-inflammatory cytokines including IL-6, IL-1β, TNF-α and IL-17A in AD mice [ 97 ].…”