Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cognitive impairment that currently is uncurable. Previous study shows that trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect in experimental models of AD. In the present study we investigated the molecular mechanisms underlying the beneficial effect of TLB on experimental models of AD in vivo and in vitro. APP/PS1 transgenic mice were administered TLB (4, 8 mg· kg−1 ·d−1, i.g.) for 3 months; rats were subjected to ICV injection of Aβ25-35, followed by administration of TLB (2.5, 5, 10 mg· kg−1 ·d−1, i.g.) for 14 days. We showed that TLB administration significantly and dose-dependently ameliorated the cognitive deficits in the two AD animal models, assessed in open field test, novel object recognition test, Y-maze test and Morris water maze test. Furthermore, TLB administration dose-dependently inhibited microglia and astrocyte activation in the hippocampus of APP/PS1 transgenic mice accompanied by decreased expression of high-mobility group box 1 (HMGB1), TLR4 and NF-κB. In Aβ25-25-treated BV2 cells, TLB (12.5−50 μM) concentration-dependently increased the cell viability through inhibiting HMGB1/TLR4/NF-κB signaling pathway. HMGB1 overexpression abrogated the beneficial effects of TLB on BV2 cells after Aβ25-35 insults. Molecular docking and surface plasmon resonance assay revealed that TLB directly bound to HMGB1 with a KD value of 8.541×10−4 M. Furthermore, we demonstrated that TLB inhibited Aβ25-35-induced acetylation of HMGB1 through activating SIRT3/SOD2 signaling pathway, thereby restoring redox homeostasis and suppressing neuroinflammation. These results, for the first time, unravel a new property of TLB: rescuing cognitive impairment of AD via targeting HMGB1 and activating SIRT3/SOD2 signaling pathway.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Dujardin S, Commins C, Lathuiliere A, Beerepoot P, Fernandes AR, Kamath TV, et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease. Nat Med. 2020;26:1256–63.
Wang P, Wang F, Ni L, Wu P, Chen J. Targeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder. Acta Pharm Sin B. 2021;11:599–608.
Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Dore V, et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature. 2018;554:249–54.
Jiang X, Lu H, Li J, Liu W, Wu Q, Xu Z, et al. A natural BACE1 and GSK3beta dual inhibitor Notopterol effectively ameliorates the cognitive deficits in APP/PS1 Alzheimer’s mice by attenuating amyloid-beta and tau pathology. Clin Transl Med. 2020;10:e50.
Zhang F, Gannon M, Chen Y, Yan S, Zhang S, Feng W, et al. Beta-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3beta/tau cascade. Sci Transl Med. 2020;16:e044769.
Rajendran L, Paolicelli RC. Microglia-mediated synapse loss in Alzheimer’s disease. J Neurosci: Off J Soc Neurosci. 2018;38:2911–9.
Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–72.
Tao CC, Cheng KM, Ma YL, Hsu WL, Chen YC, Fuh JL, et al. Galectin-3 promotes Abeta oligomerization and Abeta toxicity in a mouse model of Alzheimer’s disease. Cell Death Differ. 2020;27:192–209.
Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019;22:719–28.
Ding B, Lin C, Liu Q, He Y, Ruganzu JB, Jin H, et al. Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-kappaB signaling pathway in vivo and in vitro. J Neuroinflammation. 2020;17:302.
Huebener P, Pradere JP, Hernandez C, Gwak GY, Caviglia JM, Mu X, et al. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J Clin Invest. 2019;130:1802.
Tanaka H, Homma H, Fujita K, Kondo K, Yamada S, Jin X, et al. YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology. Nat Commun. 2020;11:507.
Huang CM, Cai JJ, Jin SW, Lin QC, Fang QJ, Nan K, et al. Class IIa HDAC downregulation contributes to surgery-induced cognitive impairment through HMGB1-mediated inflammatory response in the hippocampi of aged mice. J Inflamm Res. 2021;14:2301–15.
Peng Y, Gao P, Shi L, Chen L, Liu J, Long J. Central and peripheral metabolic defects contribute to the pathogenesis of Alzheimer’s disease: targeting mitochondria for diagnosis and prevention. Antioxid Redox Signal. 2020;32:1188–236.
Ruggeri FS, Habchi J, Chia S, Horne RI, Vendruscolo M, Knowles TPJ. Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Abeta42 oligomers. Nat Commun. 2021;12:688.
Park MH, Lee M, Nam G, Kim M, Kang J, Choi BJ, et al. N,N’-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci USA. 2019;116:23426–36.
Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, et al. Author correction: Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24:1627.
Patel D, Roy A, Kundu M, Jana M, Luan CH, Gonzalez FJ, et al. Aspirin binds to PPARalpha to stimulate hippocampal plasticity and protect memory. Proc Natl Acad Sci USA. 2018;115:E7408–17.
Zhu Y, Wan L, Li W, Ni D, Zhang W, Yan X, et al. Recent advances on 2’-fucosyllactose: physiological properties, applications, and production approaches. Crit Rev Food Sci Nutr. 2020;12:1–10.
Shang A, Liu HY, Luo M, Xia Y, Yang X, Li HY, et al. Sweet tea (Lithocarpus polystachyus rehd.) as a new natural source of bioactive dihydrochalcones with multiple health benefits. Crit Rev Food Sci Nutr. 2020;29:917–34.
Smith RL, Waddell WJ, Cohen SM, Fukushima S, Gooderham NJ, Hecht SS, et al. GRAS favoring substances 25. Food Technol. 2011;65:44–75.
Yin S, Zhang X, Lai F, Liang T, Wen J, Lin W, et al. Trilobatin as an HIV-1 entry inhibitor targeting the HIV-1 Gp41 envelope. FEBS Lett. 2018;592:2361–77.
Wang L, Liu M, Yin F, Wang Y, Li X, Wu Y, et al. Trilobatin, a novel SGLT1/2 inhibitor, selectively induces the proliferation of human hepatoblastoma cells. Molecules. 2019;24:3390.
Fan X, Zhang Y, Dong H, Wang B, Ji H, Liu X. Trilobatin attenuates the LPS-mediated inflammatory response by suppressing the NF-kappaB signaling pathway. Food Chem. 2015;166:609–15.
Gao J, Chen N, Li N, Xu F, Wang W, Lei Y, et al. Neuroprotective effects of trilobatin, a novel naturally occurring Sirt3 agonist from lithocarpus polystachyus rehd., mitigate cerebral ischemia/reperfusion injury: involvement of TLR4/NF-kappaB and Nrf2/Keap-1 signaling. Antioxid Redox Signal. 2020;33:117–43.
Li N, Li X, Shi YL, Gao JM, He YQ, Li F, et al. Trilobatin, a component from Lithocarpus polystachyrus Rehd., increases longevity in C. elegans through activating SKN1/SIRT3/DAF16 signaling pathway. Front Pharmacol. 2021;12:655045.
Chen N, Wang J, He Y, Xu Y, Zhang Y, Gong Q, et al. Trilobatin protects against Abeta25-35-induced hippocampal HT22 cells apoptosis through mediating ROS/p38/Caspase 3-dependent pathway. Front Pharmacol. 2020;11:584.
Ding J, Huang J, Yin D, Liu T, Ren Z, Hu S, et al. Trilobatin alleviates cognitive deficits and pathologies in an Alzheimer’s disease mouse model. Oxid Med Cell Longev. 2021;2021:3298400.
Lv J, Wang W, Zhu X, Xu X, Yan Q, Lu J, et al. DW14006 as a direct AMPKalpha1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation. Brain Behav Immun. 2020;90:55–69.
Gong QH, Wang Q, Pan LL, Liu XH, Xin H, Zhu YZ. S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NF-kappaB pathway in rats. Brain Behav Immun. 2011;25:110–9.
Gao J, Long L, Xu F, Feng L, Liu Y, Shi J, et al. Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase-3beta-mediated activation of autophagy. Br J Pharmacol. 2020;177:1434–52.
Yagensky O, Kohansal-Nodehi M, Gunaseelan S, Rabe T, Zafar S, Zerr I, et al. Increased expression of heme-binding protein 1 early in Alzheimer’s disease is linked to neurotoxicity. Elife. 2019;8:e47498.
Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, et al. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci. 2018;21:72–80.
Wang CY, Zhang Q, Xun Z, Yuan L, Li R, Li X, et al. Increases of iASPP-Keap1 interaction mediated by syringin enhance synaptic plasticity and rescue cognitive impairments via stabilizing Nrf2 in Alzheimer’s models. Redox Biol. 2020;36:101672.
Heckmann BL, Teubner BJW, Tummers B, Boada-Romero E, Harris L, Yang M, et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell. 2019;178:536–51.e14.
Lim SL, Tran DN, Zumkehr J, Chen C, Ghiaar S, Kieu Z, et al. Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer’s disease-like neuropathology. Glia. 2018;66:2700–18.
Milton RH, Abeti R, Averaimo S, DeBiasi S, Vitellaro L, Jiang L, et al. CLIC1 function is required for beta-amyloid-induced generation of reactive oxygen species by microglia. J Neurosci: Off J Soc Neurosci. 2008;28:11488–99.
Liu MB, Wang W, Gao JM, Li F, Shi JS, Gong QH. Icariside II attenuates cerebral ischemia/reperfusion-induced blood-brain barrier dysfunction in rats via regulating the balance of MMP9/TIMP1. Acta Pharmacol Sin. 2020;41:1547–56.
Ge X, Tang P, Rong Y, Jiang D, Lu X, Ji C, et al. Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-kappaB signaling pathway in vascular endothelial cells after traumatic spinal cord injury. Redox Biol. 2021;41:101932.
Lee JY, Han SH, Park MH, Song IS, Choi MK, Yu E, et al. N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease. Nat Commun. 2020;11:2358.
Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29:787–803.
Lewcock JW, Schlepckow K, Di Paolo G, Tahirovic S, Monroe KM, Haass C. Emerging microglia biology defines novel therapeutic approaches for Alzheimer’s disease. Neuron. 2020;108:801–21.
Hou K, Zhao J, Wang H, Li B, Li K, Shi X, et al. Chiral gold nanoparticles enantioselectively rescue memory deficits in a mouse model of Alzheimer’s disease. Nat Commun. 2020;11:4790.
Gunesch S, Hoffmann M, Kiermeier C, Fischer W, Pinto AFM, Maurice T, et al. 7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo. Redox Biol. 2020;29:101378.
Gasparotto J, Girardi CS, Somensi N, Ribeiro CT, Moreira JCF, Michels M, et al. Receptor for advanced glycation end products mediates sepsis-triggered amyloid-beta accumulation, Tau phosphorylation, and cognitive impairment. J Biol Chem. 2018;293:226–44.
Xu B, Zang SC, Li SZ, Guo JR, Wang JF, Wang D, et al. HMGB1-mediated differential response on hippocampal neurotransmitter disorder and neuroinflammation in adolescent male and female mice following cold exposure. Brain Behav Immun. 2019;76:223–35.
Xu X, Piao HN, Aosai F, Zeng XY, Cheng JH, Cui YX, et al. Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-kappaB and TNF-alpha/TNFR1/NF-kappaB pathways. Br J Pharmacol. 2020;177:5224–45.
Moghadam F, LeGraw R, Velazquez JJ, Yeo NC, Xu C, Park J, et al. Synthetic immunomodulation with a CRISPR super-repressor in vivo. Nat Cell Biol. 2020;22:1143–54.
Pan RY, Ma J, Kong XX, Wang XF, Li SS, Qi XL, et al. Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-beta clearance. Sci Adv. 2019;5:eaau6328.
Zrzavy T, Schwaiger C, Wimmer I, Berger T, Bauer J, Butovsky O, et al. Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury. Brain. 2021;144:144–61.
Zhao Y, Zhang J, Zheng Y, Zhang Y, Zhang XJ, Wang H, et al. NAD(+) improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1alpha pathway. J Neuroinflammation. 2021;18:207.
This work was supported by Science and Technology Support Plan of Guizhou Province (No. 1Y010), Innovative Research Team of comprehensive utilization with Lithocarpus polystachyus Rehd. sweet tea in Zunyi City (No. 4), Zunyi Science and Technology Project (No. 187), Program for Changjiang Scholars and Innovative Research Team in University, China (No. IRT_17R113).
The authors declare no competing interests.
About this article
Cite this article
Gao, Jm., Zhang, X., Shu, Gt. et al. Trilobatin rescues cognitive impairment of Alzheimer’s disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway. Acta Pharmacol Sin 43, 2482–2494 (2022). https://doi.org/10.1038/s41401-022-00888-5
- Alzheimer’s disease
- oxidative stress