We demonstrated that Honokiol (HKL), a natural compound from Magnolia officinalis, exerts neuroprotection in APP/PS1 mice by increasing the expression of Sirtuin 3 (SIRT3), which activates mitochondrial autophagy. We also found that the liver may play a significant role in the pathogenesis of Alzheimer's disease (AD). However, it remains unclear whether HKL exerts its protection on AD through hepatic pathways.
Objective
We aimed to elucidate the impact of HKL on the liver of AD mice and its mechanisms.
Methods
APP/PS1 transgenic mice were utilized as AD models and administered with HKL and 3-TYP (an inhibitor of SIRT3). Congo-red staining and immunohistochemistry were conducted to detect the Aβ1–42 plaque deposition in the brain. Hematoxylin-eosin and Oil red O staining were employed to observe alterations in hepatic morphology. Liver function markers were tested to assess the metabolic function. qRT-PCR was employed to examine the level of SIRT3 mRNA. Western blot was performed to evaluate the expression of SIRT3, insulin degrading enzyme (IDE), GpLD1, lipoprotein receptor related protein 1 (LRP-1), ANGPTL8, and superoxide dismutase 2 (SOD2).
Results
HKL mitigated the Aβ1–42 plaque deposition in the brains of AD mice. It also reduced hepatic morphological damage. Additionally, HKL decreased the levels of ALT, AST, ALP, TBIL, and DBIL, and enhanced the levels of TP and ALB. It increased the levels of SIRT3 mRNA, and also the expression of SIRT3, IDE, GpLD1, and SOD2, while suppressing the expression of LRP-1 and ANGPTL8. 3-TYP could reverse all these effects of HKL on AD mice.
Conclusions
HKL might alleviate liver damage of AD mice by upregulating SIRT3.
HanSWParkYHJangES, et al.Implications of liver enzymes in the pathogenesis of Alzheimer's disease. J Alzheimers Dis2022; 88: 1371–1376.
2.
GaoPYOuYNHuangYM, et al.Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: the CABLE study. J Neurochem2024; 168: 39–51.
3.
MaCHongFYangS. Amyloidosis in Alzheimer's disease: pathogeny, etiology, and related therapeutic directions. Molecules2022; 27: 1210.
4.
ClarkeJRRibeiroFCFrozzaRL, et al.Metabolic dysfunction in Alzheimer's disease: from basic neurobiology to clinical approaches. J Alzheimers Dis2018; 64: S405–S426.
5.
ChengYHeCYTianDY, et al.Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease. Acta Neuropathol2023; 145: 717–731.
6.
ZhengHCaiAShuQ, et al.Tissue-specific metabolomics analysis identifies the liver as a major organ of metabolic disorders in amyloid precursor protein/presenilin 1 mice of Alzheimer's disease. J Proteome Res2019; 18: 1218–1227.
7.
LuYPikeJRHoogeveenRC, et al.Liver integrity and the risk of Alzheimer's disease and related dementias. Alzheimers Dement2024; 20: 1913–1922.
8.
ChiuWCTsanYTTsaiSL, et al.Hepatitis C viral infection and the risk of dementia. Eur J Neurol2014; 21: 1068–e1059.
9.
ParikhNSKamelHZhangC, et al.Association between liver fibrosis and incident dementia in the UK biobank study. Eur J Neurol2022; 29: 2622–2630.
10.
LiHJiaJWangW, et al.Honokiol alleviates cognitive deficits of Alzheimer's disease (PS1V97L) transgenic mice by activating mitochondrial SIRT3. J Alzheimers Dis2018; 64: 291–302.
11.
DobrekLGłowackaK. Depression and its phytopharmacotherapy-A narrative review. Int J Mol Sci2023; 24: 4772.
12.
LiWWangSZhangH, et al.Honokiol restores microglial phagocytosis by reversing metabolic reprogramming. J Alzheimers Dis2021; 82: 1475–1485.
13.
WangDDongXWangC. Honokiol ameliorates amyloidosis and neuroinflammation and improves cognitive impairment in Alzheimer's disease transgenic mice. J Pharmacol Exp Ther2018; 366: 470–478.
14.
SasiaCBorgonettiVManciniC, et al.The Neolignan Honokiol and its synthetic derivative Honokiol hexafluoro reduce neuroinflammation and cellular senescence in microglia cells. Cells2024; 13: 1652.
15.
XieZZhaoJWangH, et al.Magnolol alleviates Alzheimer's disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-γ. Biomed Pharmacother2020; 124: 109886.
16.
HouMBaoWGaoY, et al.Honokiol improves cognitive impairment in APP/PS1 mice through activating mitophagy and mitochondrial unfolded protein response. Chem Biol Interact2022; 351: 109741.
17.
YingYLuCChenC, et al.SIRT3 Regulates neuronal excitability of Alzheimer's disease models in an oxidative stress-dependent manner. Neuromolecular Med2022; 24: 261–267.
18.
MukherjeeSMoJPaolellaLM, et al.SIRT3 Is required for liver regeneration but not for the beneficial effect of nicotinamide riboside. JCI Insight2021; 6: e147193.
19.
LiRXinTLiD, et al.Therapeutic effect of sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol2018; 18: 229–243.
20.
LiHSunJWuY, et al.Honokiol relieves hippocampal neuronal damage in Alzheimer's disease by activating the SIRT3-mediated mitochondrial autophagy. CNS Neurosci Ther2024; 30: e14878.
21.
PanYOmoriKAliI, et al.Altered expression of small intestinal drug transporters and hepatic metabolic enzymes in a mouse model of familial Alzheimer's disease. Mol Pharm2018; 15: 4073–4083.
22.
YuanSWangYYangJ, et al.Treadmill exercise can regulate the redox balance in the livers of APP/PS1 mice and reduce LPS accumulation in their brains through the gut-liver-kupffer cell axis. Aging (Albany NY)2024; 16: 1374–1389.
23.
WuKLiCLiuK, et al.Effect of high plasma levels of Aβ42 on the liver of APP/PS1 transgenic AD mice. Chin J Alzheimers Dis Relat Disord2022; 5: 38–41.
24.
AshrafianHZadehEHKhanRH. Review on Alzheimer's disease: inhibition of amyloid beta and tau tangle formation. Int J Biol Macromol2021; 167: 382–394.
25.
LiNLiangYZhangL, et al.Neolignans in Magnolia officinalis as natural anti-Alzheimer's disease agents: a systematic review. Ageing Res Rev2024; 99: 102398.
26.
WuKXuCQiuG, et al.Association of lower liver function with cognitive impairment in the Shenzhen ageing-related disorder cohort in China. Front Aging Neurosci2022; 14: 1012219.
27.
WangHShiLLuoS, et al.Associations of serum liver function with cerebral blood flow in patients with Alzheimer's disease. J Alzheimers Dis Rep2024; 8: 437–445.
28.
KraupnerNDinhCPWenX, et al.Identification of indole-based activators of insulin degrading enzyme. Eur J Med Chem2022; 228: 113982.
29.
KulasJAFranklinWFSmithNA, et al.Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues. Am J Physiol Endocrinol Metab2019; 316: E106–E120.
30.
LiXShiXMcPhersonM, et al.Cap-independent translation of GPLD1 enhances markers of brain health in long-lived mutant and drug-treated mice. Aging Cell2022; 21: e13685.
31.
RenTHeJZhangT, et al.Exercise activates interferon response of the liver via Gpld1 to enhance antiviral innate immunity. Sci Adv2024; 10: eadk5011.
32.
HorowitzAMFanXBieriG, et al.Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science2020; 369: 167–173.
33.
ShinoharaMTachibanaMKanekiyoT, et al.Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies. J Lipid Res2017; 58: 1267–1281.
34.
PetrallaSPanayotovaMFranchinaE, et al.Low-density lipoprotein receptor-related protein 1 as a potential therapeutic target in Alzheimer's disease. Pharmaceutics2024; 16: 948.
35.
SehgalNGuptaAValliRK, et al.Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A2012; 109: 3510–3515.
36.
DonahueJEFlahertySLJohansonCE, et al.RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. Acta Neuropathol2006; 112: 405–415.
37.
JeynesBProviasJ. Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. Curr Alzheimer Res2008; 5: 432–437.
38.
GaoLWangJJiangY, et al.Relationship between peripheral transport proteins and plasma amyloid-β in patients with Alzheimer's disease were different from cognitively normal controls: a propensity score matching analysis. J Alzheimers Dis2020; 78: 699–709.
39.
StorelliFBillingtonSKumarAR, et al.Abundance of P-glycoprotein and other drug transporters at the human blood-brain barrier in Alzheimer's disease: a quantitative targeted proteomic study. Clin Pharmacol Ther2021; 109: 667–675.
40.
LiDPHuangLKanRR, et al.LILRB2/PirB Mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis. Nat Commun2023; 14: 4436.
41.
VanGuilder StarkeyHDVan KirkCABixlerGV, et al.Neuroglial expression of the MHCI pathway and PirB receptor is upregulated in the hippocampus with advanced aging. J Mol Neurosci2012; 48: 111–126.
42.
MengXLiDKanR, et al.Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway. J Neuroinflammation2024; 21: 192.
43.
PanRYMaJKongXX, et al.Sodium rutin ameliorates Alzheimer's disease-like pathology by enhancing microglial amyloid-β clearance. Sci Adv2019; 5: eaau6328.
44.
OlajideOJLa RueCBergdahlA, et al.Inhibiting amyloid beta (1–42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex. Front Aging Neurosci2022; 14: 960314.
45.
TéglásTÁbrahámDJókaiM, et al.Exercise combined with a probiotics treatment alters the microbiome, but moderately affects signalling pathways in the liver of male APP/PS1 transgenic mice. Biogerontology2020; 21: 807–815.
46.
TalarekSListosJBarrecaD, et al.Neuroprotective effects of honokiol: from chemistry to medicine. Biofactors2017; 43: 760–769.
47.
GaoJMZhangXShuGT, et al.Trilobatin rescues cognitive impairment of Alzheimer's disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway. Acta Pharmacol Sin2022; 43: 2482–2494.
48.
PengYGaoPShiL, et al.Central and peripheral metabolic defects contribute to the pathogenesis of Alzheimer's disease: targeting mitochondria for diagnosis and prevention. Antioxid Redox Signal2020; 32: 1188–1236.
49.
RameshSGovindarajuluMLyndT, et al.SIRT3 Activator honokiol attenuates β-amyloid by modulating amyloidogenic pathway. PLoS One2018; 13: e0190350.
50.
PeroneIGhenaNWangJ, et al.Mitochondrial SIRT3 deficiency results in neuronal network hyperexcitability, accelerates age-related Aβ pathology, and renders neurons vulnerable to Aβ toxicity. Neuromolecular Med2023; 25: 27–39.
