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Volume 23, Issue 6
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Background

Alzheimer's Disease (AD) is the most common dementia in clinics. Despite decades of progress in the study of the pathogenesis of AD, clinical treatment strategies for AD remain lacking. Apigenin, a natural flavonoid compound, is present in a variety of food and Chinese herbs and has been proposed to have a wide range of therapeutic effects on dementia.

Objective

To clarify the relevant pharmacological mechanism and therapeutic effect of apigenin on animal models of AD.

Methods

Computer-based searches of the PubMed, Cochrane Library, Embase, and Web of Science databases were used to identify preclinical literature on the use of apigenin for treating AD. All databases were searched from their respective inception dates until June 2023. The meta-analysis was performed with Review manager 5.4.1 and STATA 17.0.

Results

Thirteen studies were eventually enrolled, which included 736 animals in total. Meta-analysis showed that apigenin had a positive effect on AD. Compared to controls, apigenin treatment reduced escape latency, increased the percentage of time spent in the target quadrant and the number of plateaus traversed; apigenin was effective in reducing nuclear factor kappa-B (NF-κB) p65 levels; apigenin effectively increased antioxidant molecules SOD and GSH-px and decreased oxidative index MDA; for ERK/CREB/BDNF pathway, apigenin effectively increased BDNF and pCREB molecules; additionally, apigenin effectively decreased caspase3 levels and the number of apoptotic cells in the hippocampus.

Conclusion

The results show some efficacy of apigenin in the treatment of AD models. However, further clinical studies are needed to confirm the clinical efficacy of apigenin.

© 2025 Bentham Science Publishers
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2025-04-26

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References

  1. GoldfarbD. SheardS. ShaughnessyL. AtriA. Disclosure of alzheimer’s disease and dementia. J. Clin. Psychiatry,2019802MS18002BR1C10.4088/JCP.MS18002BR1C30900850
     [Google Scholar]
  2. Soria LopezJ.A. GonzálezH.M. LégerG.C. Alzheimer’s disease.Handb. Clin. Neurol.201916723125510.1016/B978‑0‑12‑804766‑8.00013‑3 31753135
     [Google Scholar]
  3. BenmeloukaA.Y. OuerdaneY. OutaniO. AlnasserY.T. AlghamdiB.S. PerveenA. AshrafG.M. EbadaM.A. Alzheimer’s disease-related psychosis: An overview of clinical manifestations, pathogenesis, and current treatment.Curr. Alzheimer Res.202219428530110.2174/1567205019666220418151914 35440308
     [Google Scholar]
  4. YangA. WuJ. ChenY. ShenR. KouX. Study on multi-target synergistic treatment of alzheimer’s disease based on metal chelators.Curr. Drug Targets2022242131150 36165518
     [Google Scholar]
  5. ShahH. AlbaneseE. DugganC. RudanI. LangaK.M. CarrilloM.C. ChanK.Y. JoanetteY. PrinceM. RossorM. SaxenaS. SnyderH.M. SperlingR. VargheseM. WangH. WortmannM. DuaT. Research priorities to reduce the global burden of dementia by 2025.Lancet Neurol.201615121285129410.1016/S1474‑4422(16)30235‑6 27751558
     [Google Scholar]
  6. RostagnoA.A. Pathogenesis of alzheimer’s disease.Int. J. Mol. Sci.202224110710.3390/ijms24010107 36613544
     [Google Scholar]
  7. CalabreseV. GiordanoJ. SignorileA. Laura OntarioM. CastorinaS. De PasqualeC. EckertG. CalabreseE.J. Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection.J. Neurosci. Res.201694121588160310.1002/jnr.23925 27662637
     [Google Scholar]
  8. LongJ.M. HoltzmanD.M. Alzheimer disease: An update on pathobiology and treatment strategies.Cell2019179231233910.1016/j.cell.2019.09.001 31564456
     [Google Scholar]
  9. LaneC.A. HardyJ. SchottJ.M. Alzheimer’s disease.Eur. J. Neurol.2018251597010.1111/ene.13439 28872215
     [Google Scholar]
  10. Milà-AlomàM. AshtonN.J. ShekariM. SalvadóG. Ortiz-RomeroP. Montoliu-GayaL. BenedetA.L. KarikariT.K. Lantero-RodriguezJ. VanmechelenE. DayT.A. González-EscalanteA. Sánchez-BenavidesG. MinguillonC. FauriaK. MolinuevoJ.L. DageJ.L. ZetterbergH. GispertJ.D. Suárez-CalvetM. BlennowK. Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease.Nat. Med.20222891797180110.1038/s41591‑022‑01925‑w 35953717
     [Google Scholar]
  11. MukhopadhyayS. BanerjeeD. A primer on the evolution of aducanumab: The first antibody approved for treatment of alzheimer’s disease.J. Alzheimers Dis.20218341537155210.3233/JAD‑215065 34366359
     [Google Scholar]
  12. KnopmanD.S. JonesD.T. GreiciusM.D. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019.Alzheimers Dement.202117469670110.1002/alz.12213 33135381
     [Google Scholar]
  13. CummingsJ. RabinoviciG.D. AtriA. AisenP. ApostolovaL.G. HendrixS. SabbaghM. SelkoeD. WeinerM. SallowayS. Aducanumab: Appropriate use recommendations update.J. Prev. Alzheimers Dis.202292221230 35542993
     [Google Scholar]
  14. DhaddaS. KanekiyoM. LiD. SwansonC.J. IrizarryM. BerryS. KramerL.D. BerryD.A. Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer’s disease.Alzheimers Res. Ther.202214118210.1186/s13195‑022‑01129‑x 36482412
     [Google Scholar]
  15. SwansonC.J. ZhangY. DhaddaS. WangJ. KaplowJ. LaiR.Y.K. LannfeltL. BradleyH. RabeM. KoyamaA. ReydermanL. BerryD.A. BerryS. GordonR. KramerL.D. CummingsJ.L. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody.Alzheimers Res. Ther.20211318010.1186/s13195‑021‑00813‑8 33865446
     [Google Scholar]
  16. van DyckC.H. SwansonC.J. AisenP. BatemanR.J. ChenC. GeeM. KanekiyoM. LiD. ReydermanL. CohenS. FroelichL. KatayamaS. SabbaghM. VellasB. WatsonD. DhaddaS. IrizarryM. KramerL.D. IwatsuboT. Lecanemab in early alzheimer’s disease.N. Engl. J. Med.2023388192110.1056/NEJMoa2212948 36449413
     [Google Scholar]
  17. MarucciG. BuccioniM. BenD.D. LambertucciC. VolpiniR. AmentaF. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease.Neuropharmacology202119010835210.1016/j.neuropharm.2020.108352 33035532
     [Google Scholar]
  18. CummingsJ.L. TongG. BallardC. Treatment combinations for alzheimer’s disease: Current and future pharmacotherapy options.J. Alzheimers Dis.201967377979410.3233/JAD‑180766 30689575
     [Google Scholar]
  19. MirR.H. ShahA.J. Mohi-Ud-DinR. PottooF.H. DarM.A. JachakS.M. MasoodiM.H. Natural anti-inflammatory compounds as drug candidates in alzheimers disease.Curr. Med. Chem.202128234799482510.2174/1875533XMTA4aNzUBx 32744957
     [Google Scholar]
  20. TaylorE. KimY. ZhangK. ChauL. NguyenB.C. RayalamS. WangX. Antiaging mechanism of natural compounds: Effects on autophagy and oxidative stress.Molecules20222714439610.3390/molecules27144396 35889266
     [Google Scholar]
  21. FerreiraJ.P.S. AlbuquerqueH.M.T. CardosoS.M. SilvaA.M.S. SilvaV.L.M. Dual-target compounds for Alzheimer’s disease: Natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR).Eur. J. Med. Chem.202122111349210.1016/j.ejmech.2021.113492 33984802
     [Google Scholar]
  22. RománG.C. JacksonR.E. GadhiaR. RománA.N. ReisJ. Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease.Rev. Neurol.20191751072474110.1016/j.neurol.2019.08.005 31521398
     [Google Scholar]
  23. KolaA. ValensinD. DudekD. Metal complexation mechanisms of polyphenols associated to alzheimer’s disease.Curr. Med. Chem.202128357278729410.2174/0929867328666210729120242 34325628
     [Google Scholar]
  24. DabeekW.M. MarraM.V. Dietary quercetin and kaempferol: Bioavailability and potential cardiovascular-related bioactivity in humans.Nutrients20191110228810.3390/nu11102288 31557798
     [Google Scholar]
  25. ShimazuR. AnadaM. MiyaguchiA. NomiY. MatsumotoH. Evaluation of blood-brain barrier permeability of polyphenols, anthocyanins, and their metabolites.J. Agric. Food Chem.20216939116761168610.1021/acs.jafc.1c02898 34555897
     [Google Scholar]
  26. SalehiB. VendittiA. Sharifi-RadM. KręgielD. Sharifi-RadJ. DurazzoA. LucariniM. SantiniA. SoutoE. NovellinoE. AntolakH. AzziniE. SetzerW. MartinsN. The therapeutic potential of apigenin.Int. J. Mol. Sci.2019206130510.3390/ijms20061305 30875872
     [Google Scholar]
  27. WangM. FirrmanJ. LiuL. YamK. A review on flavonoid apigenin: Dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota.BioMed Res. Int.2019201911810.1155/2019/7010467 31737673
     [Google Scholar]
  28. KootiW. DaraeiN. A review of the antioxidant activity of celery (Apium graveolens L).J. Evid. Based Complementary Altern. Med.20172241029103410.1177/2156587217717415 28701046
     [Google Scholar]
  29. ShankarE. GoelA. GuptaK. GuptaS. Plant flavone apigenin: An emerging anticancer agent.Curr. Pharmacol. Rep.20173642344610.1007/s40495‑017‑0113‑2 29399439
     [Google Scholar]
  30. AdelM. ZahmatkeshanM. AkbarzadehA. RabieeN. AhmadiS. KeyhanvarP. RezayatS.M. SeifalianA.M. Chemotherapeutic effects of Apigenin in breast cancer: Preclinical evidence and molecular mechanisms; enhanced bioavailability by nanoparticles.Biotechnol. Rep. 202234e0073010.1016/j.btre.2022.e00730 35686000
     [Google Scholar]
  31. ZhangZ. CuiC. WeiF. LvH. Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system.Drug Dev. Ind. Pharm.20174381276128210.1080/03639045.2017.1313857 28358225
     [Google Scholar]
  32. SenK. BanerjeeS. MandalM. Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer.Colloids Surf. B Biointerfaces201918092210.1016/j.colsurfb.2019.04.035 31015105
     [Google Scholar]
  33. XuR. JiangC. ZhouL. LiB. HuY. GuoY. XiaoX. LuS. Fabrication of stable apigenin nanosuspension with peg 400 as antisolvent for enhancing the solubility and bioavailability.AAPS PharmSciTech20222311210.1208/s12249‑021‑02164‑x 34881399
     [Google Scholar]
  34. WangX. LiJ. ZhaoD. LiJ. |Therapeutic and preventive effects of apigenin in cerebral ischemia: A review.Food Funct.20221322114251143710.1039/D2FO02599J 36314275
     [Google Scholar]
  35. ChuangC.M. MonieA. WuA. HungC.F. Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects.J. Biomed. Sci.20091614910.1186/1423‑0127‑16‑49 19473507
     [Google Scholar]
  36. RahimiA. AlimohammadiM. FaramarziF. Alizadeh-NavaeiR. RafieiA. The effects of apigenin administration on the inhibition of inflammatory responses and oxidative stress in the lung injury models: A systematic review and meta-analysis of preclinical evidence.Inflammopharmacology20223041259127610.1007/s10787‑022‑00994‑0 35661071
     [Google Scholar]
  37. ZhaoL. WangJ.L. LiuR. LiX.X. LiJ.F. ZhangL. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model.Molecules20131889949996510.3390/molecules18089949 23966081
     [Google Scholar]
  38. ZhaoL. WangJ. WangY. FaX. Apigenin attenuates copper-mediated β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model.Brain Res.20131492334510.1016/j.brainres.2012.11.019 23178511
     [Google Scholar]
  39. de Font-Réaulx RojasE. Dorazco-BarraganG. [Clinical stabilisation in neurodegenerative diseases: Clinical study in phase IIRev. Neurol.2010509520528 20443170
     [Google Scholar]
  40. MünchG. VenigallaM. SonegoS. GyengesiE. Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer′s disease.Neural Regen. Res.20151081181118510.4103/1673‑5374.162686 26487830
     [Google Scholar]
  41. SalamehJ.P. BossuytP.M. McGrathT.A. ThombsB.D. HydeC.J. MacaskillP. DeeksJ.J. LeeflangM. KorevaarD.A. WhitingP. TakwoingiY. ReitsmaJ.B. CohenJ.F. FrankR.A. HuntH.A. HooftL. RutjesA.W.S. WillisB.H. GatsonisC. LevisB. MoherD. McInnesM.D.F. Preferred reporting items for systematic review and meta-analysis of diagnostic test accuracy studies (PRISMA-DTA): Explanation, elaboration, and checklist.BMJ2020370m263210.1136/bmj.m2632 32816740
     [Google Scholar]
  42. HooijmansC.R. RoversM.M. de VriesR.B.M. LeenaarsM. Ritskes-HoitingaM. LangendamM.W. SYRCLE’s risk of bias tool for animal studies.BMC Med. Res. Methodol.20141414310.1186/1471‑2288‑14‑43 24667063
     [Google Scholar]
  43. YamauraK. NelsonA.L. NishimuraH. RutledgeJ.C. RavuriS.K. BahneyC. PhilipponM.J. HuardJ. The effects of losartan or angiotensin II receptor antagonists on cartilage: A systematic review.Osteoarthritis Cartilage2023314435446 36586717
     [Google Scholar]
  44. AlsadatA.M. NikbakhtF. Hossein NiaH. GolabF. KhademY. BaratiM. VazifekhahS. GSK-3β as a target for apigenin-induced neuroprotection against Aβ 25-35 in a rat model of Alzheimer’s disease.Neuropeptides20219010220010.1016/j.npep.2021.102200 34597878
     [Google Scholar]
  45. LiuR. ZhangT. YangH. LanX. YingJ. DuG. The flavonoid apigenin protects brain neurovascular coupling against amyloid-beta(2)(5)(-)(3)(5)-induced toxicity in mice.J. Alzheimers Dis.20112418510010.3233/JAD‑2010‑101593 21297270
     [Google Scholar]
  46. NikbakhtF. KhademY. HaghaniS. HoseininiaH. Moein SadatA. HeshemiP. JamaliN. Protective role of apigenin against Aβ 25-35 toxicity via inhibition of mitochondrial cytochrome c release.Basic Clin. Neurosci.2019106557566 32477473
     [Google Scholar]
  47. FanH. KangK. LiZ. Effects of apigenin on oxidative stress and inflammatory reaction in hippocampus of rats with alzheimer’s disease induced by Aβ 1 - 42. Acta.Chinese. Med.20233803602608
     [Google Scholar]
  48. JameieS.B. PirastehA. NaseriA. JameieM.S. FarhadiM. BabaeeJ.F. ElyasiL. β-amyloid formation, memory, and learning decline following long-term ovariectomy and its inhibition by systemic administration of apigenin and β-estradiol.Basic Clin. Neurosci.2021123383394 34917297
     [Google Scholar]
  49. AhmedyO.A. AbdelghanyT.M. El-ShamarkaM.E.A. KhattabM.A. El-TanboulyD.M. Apigenin attenuates LPS-induced neurotoxicity and cognitive impairment in mice via promoting mitochondrial fusion/mitophagy: Role of SIRT3/PINK1/Parkin pathway.Psychopharmacology 2022239123903391710.1007/s00213‑022‑06262‑x 36287214
     [Google Scholar]
  50. ChenL. XieW. XieW. ZhuangW. JiangC. LiuN. Apigenin attenuates isoflurane-induced cognitive dysfunction via epigenetic regulation and neuroinflammation in aged rats.Arch. Gerontol. Geriatr.201773293610.1016/j.archger.2017.07.004 28743056
     [Google Scholar]
  51. KimY. KimJ. HeM. LeeA. ChoE. Apigenin ameliorates scopolamine-induced cognitive dysfunction and neuronal damage in mice.Molecules20212617519210.3390/molecules26175192 34500626
     [Google Scholar]
  52. MaoX.Y. YuJ. LiuZ.Q. ZhouH.H. Apigenin attenuates diabetes-associated cognitive decline in rats via suppressing oxidative stress and nitric oxide synthase pathway.Int. J. Clin. Exp. Med.2015891550615513 26629041
     [Google Scholar]
  53. SangY. ZhangF. WangH. YaoJ. ChenR. ZhouZ. YangK. XieY. WanT. DingH. Apigenin exhibits protective effects in a mouse model of D -galactose-induced aging via activating the Nrf2 pathway.Food Funct.2017862331234010.1039/C7FO00037E 28598487
     [Google Scholar]
  54. TahaM. EldemerdashO.M. ElshaffeiI.M. YousefE.M. SolimanA.S. SenousyM.A. Apigenin attenuates hippocampal microglial activation and restores cognitive function in methotrexate-treated rats: Targeting the miR-15a/ROCK-1/ERK1/2 Pathway.Mol. Neurobiol.20236073770378710.1007/s12035‑023‑03299‑7 36943623
     [Google Scholar]
  55. ZhaoF. DangY. ZhangR. JingG. LiangW. XieL. LiZ. Apigenin attenuates acrylonitrile-induced neuro-inflammation in rats: Involved of inactivation of the TLR4/NF-κB signaling pathway.Int. Immunopharmacol.20197510569710.1016/j.intimp.2019.105697
     [Google Scholar]
  56. TuckerL.B. VeloskyA.G. McCabeJ.T. Applications of the Morris water maze in translational traumatic brain injury research.Neurosci. Biobehav. Rev.20188818720010.1016/j.neubiorev.2018.03.010 29545166
     [Google Scholar]
  57. BalakrishnanR. ParkJ.Y. ChoD.Y. AhnJ.Y. YooD.S. SeolS.H. YoonS.H. ChoiD.K. AD-1 small molecule improves learning and memory function in scopolamine-induced amnesic mice model through regulation of CREB/BDNF and NF-κB/MAPK signaling pathway.Antioxidants202312364810.3390/antiox12030648 36978896
     [Google Scholar]
  58. MancusoC. CaponeC. RanieriS.C. FuscoS. CalabreseV. EboliM.L. PreziosiP. GaleottiT. PaniG. Bilirubin as an endogenous modulator of neurotrophin redox signaling.J. Neurosci. Res.200886102235224910.1002/jnr.21665 18338802
     [Google Scholar]
  59. PakM.E. YangH.J. LiW. KimJ.K. GoY. Yuk-Gunja-Tang attenuates neuronal death and memory impairment via ERK/CREB/BDNF signaling in the hippocampi of experimental Alzheimer’s disease model.Front. Pharmacol.202213101484010.3389/fphar.2022.1014840 36386241
     [Google Scholar]
  60. ShadfarS. ParakhS. JamaliM.S. AtkinJ.D. Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases.Transl. Neurodegener.20231211810.1186/s40035‑023‑00350‑4 37055865
     [Google Scholar]
  61. VanniS. Colini BaldeschiA. ZattoniM. LegnameG. Brain aging: A Ianus ‐faced player between health and neurodegeneration.J. Neurosci. Res.202098229931110.1002/jnr.24379 30632202
     [Google Scholar]
  62. ObengE. Apoptosis (programmed cell death) and its signals - A review.Braz. J. Biol.20218141133114310.1590/1519‑6984.228437 33111928
     [Google Scholar]
  63. ShenB. ChenH.B. ZhouH.G. WuM.H. Celastrol induces caspase-dependent apoptosis of hepatocellular carcinoma cells by suppression of mammalian target of rapamycin.J. Tradit. Chin. Med.2021413381389 34114395
     [Google Scholar]
  64. ArnaudL. BenechP. GreethamL. StephanD. JimenezA. JullienN. García-GonzálezL. TsvetkovP.O. DevredF. Sancho-MartinezI. Izpisua BelmonteJ.C. BarangerK. RiveraS. NivetE. APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation.Cell Rep.202240711120010.1016/j.celrep.2022.111200 35977506
     [Google Scholar]
  65. NafeaM. ElharounM. Abd-AlhaseebM.M. HelmyM.W. Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer’s disease: The role of TNF-α/NF-κB/IL-1β axis inhibition.Naunyn Schmiedebergs Arch. Pharmacol.2023396348549810.1007/s00210‑022‑02322‑3 36385687
     [Google Scholar]
  66. Moya-AlvaradoG. Tiburcio-FelixR. IbáñezM.R. Aguirre-SotoA.A. GuerraM.V. WuC. MobleyW.C. PerlsonE. BronfmanF.C. BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons.eLife202312e7745510.7554/eLife.77455 36826992
     [Google Scholar]
  67. SauraC.A. CardinauxJ.R. Emerging roles of CREB-regulated transcription coactivators in brain physiology and pathology.Trends Neurosci.2017401272073310.1016/j.tins.2017.10.002 29097017
     [Google Scholar]
  68. BaiL.L. ZhangL.Q. MaJ. LiJ. TianM. CaoR.J. HeX.X. HeZ.X. YuH.L. ZhuX.J. DIP2A is involved in SOD-mediated antioxidative reactions in murine brain.Free Radic. Biol. Med.202116861510.1016/j.freeradbiomed.2021.03.027 33781892
     [Google Scholar]
  69. HannaR. RozenbergA. SaiedL. Ben-YosefD. LavyT. KleifeldO. In-depth characterization of apoptosis N-terminome reveals a link between caspase-3 cleavage and posttranslational N-terminal acetylation.Mol. Cell. Proteomics202322710058410.1016/j.mcpro.2023.100584 37236440
     [Google Scholar]
  70. MishraR. PhanT. KumarP. MorrisseyZ. GuptaM. HollandsC. ShettiA. LopezK.L. Maienschein-ClineM. SuhH. HenR. LazarovO. Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by restoring the memory-storing neurons.J. Exp. Med.20222199e2022039110.1084/jem.20220391 35984475
     [Google Scholar]
  71. LuoZ. XuH. LiuL. OhulchanskyyT.Y. QuJ. Optical imaging of beta-amyloid plaques in alzheimer’s disease.Biosensors 202111825510.3390/bios11080255 34436057
     [Google Scholar]
  72. ChoY. BaeH.G. OkunE. ArumugamT.V. JoD.G. Physiology and pharmacology of amyloid precursor protein.Pharmacol. Ther.202223510812210.1016/j.pharmthera.2022.108122 35114285
     [Google Scholar]
  73. LinY. ImH. DiemL.T. HamS. Characterizing the structural and thermodynamic properties of Aβ42 and Aβ40.Biochem. Biophys. Res. Commun.2019510344244810.1016/j.bbrc.2019.01.124 30722990
     [Google Scholar]
  74. Trujillo-EstradaL. VanderklishP.W. NguyenM.M.T. KuangR.R. NguyenC. HuynhE. da CunhaC. JavonilloD.I. FornerS. MartiniA.C. SarrafS.T. SimmonV.F. Baglietto-VargasD. LaFerlaF.M. SPG302 reverses synaptic and cognitive deficits without altering amyloid or tau pathology in a transgenic model of alzheimer’s disease.Neurotherapeutics20211842468248310.1007/s13311‑021‑01143‑1 34738197
     [Google Scholar]
  75. GirotraP. BehlT. SehgalA. SinghS. BungauS. Investigation of the molecular role of brain-derived neurotrophic factor in alzheimer’s disease.J. Mol. Neurosci.202272217318610.1007/s12031‑021‑01824‑8 34424488
     [Google Scholar]
  76. FalcicchiaC. TozziF. ArancioO. WattersonD.M. OrigliaN. Involvement of p38 MAPK in synaptic function and dysfunction.Int. J. Mol. Sci.20202116562410.3390/ijms21165624 32781522
     [Google Scholar]
  77. SinghR. GaneshpurkarA. GhoshP. PokleA.V. KumarD. SinghR. SinghS.K. KumarA. Classification of beta‐site amyloid precursor protein cleaving enzyme 1 inhibitors by using machine learning methods.Chem. Biol. Drug Des.20219861079109710.1111/cbdd.13965 34592057
     [Google Scholar]
  78. SchnöderL. TomicI. SchwindtL. HelmD. RettelM. Schulz-SchaefferW. KrauseE. RettigJ. FassbenderK. LiuY. P38α‐MAPK phosphorylates Snapin and reduces Snapin‐mediated BACE1 transportation in APP‐transgenic mice.FASEB J.2021357e2169110.1096/fj.202100017R 34118085
     [Google Scholar]
  79. ChenY. HuangX. ZhangY. RockensteinE. BuG. GoldeT.E. MasliahE. XuH. Alzheimer’s β-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of β-Amyloid.J. Neurosci.20123233113901139510.1523/JNEUROSCI.0757‑12.2012 22895721
     [Google Scholar]
  80. LiY. ZhangJ. WanJ. LiuA. SunJ. Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease.Biomed. Pharmacother.202013211088710.1016/j.biopha.2020.110887 33254429
     [Google Scholar]
  81. SiddiqueY.H. Rahul; Ara, G.; Afzal, M.; Varshney, H.; Gaur, K.; Subhan, I.; Mantasha, I.; Shahid, M. Beneficial effects of apigenin on the transgenic Drosophila model of Alzheimer’s disease.Chem. Biol. Interact.202236611012010.1016/j.cbi.2022.110120 36027948
     [Google Scholar]
  82. ZhaoL. WoodyS.K. ChhibberA. Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics. Ageing Res Rev 201524(Pt B)178190
     [Google Scholar]
  83. KarranE. De StrooperB. The amyloid hypothesis in Alzheimer disease: New insights from new therapeutics.Nat. Rev. Drug Discov.202221430631810.1038/s41573‑022‑00391‑w 35177833
     [Google Scholar]
  84. LeeY.H. Im, E.; Hyun, M.; Park, J.; Chung, K.C. Protein phosphatase PPM1B inhibits DYRK1A kinase through dephosphorylation of pS258 and reduces toxic tau aggregation.J. Biol. Chem.202129610024510.1074/jbc.RA120.015574 33380426
     [Google Scholar]
  85. BaptistaF.I. HenriquesA.G. SilvaA.M.S. WiltfangJ. da Cruz e Silva, O.A.B. Flavonoids as therapeutic compounds targeting key proteins involved in Alzheimer’s disease.ACS Chem. Neurosci.201452839210.1021/cn400213r 24328060
     [Google Scholar]
  86. LiuB. LiuJ. ShiJ.S. SAMP8 mice as a model of age-related cognition decline with underlying mechanisms in alzheimer’s disease.J. Alzheimers Dis.202075238539510.3233/JAD‑200063 32310176
     [Google Scholar]
  87. Mattsson-CarlgrenN. JanelidzeS. BatemanR.J. SmithR. StomrudE. SerranoG.E. ReimanE.M. PalmqvistS. DageJ.L. BeachT.G. HanssonO. Soluble P‐tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau.EMBO Mol. Med.2021136e1402210.15252/emmm.202114022 33949133
     [Google Scholar]
  88. GratuzeM. ChenY. ParhizkarS. JainN. StricklandM.R. SerranoJ.R. ColonnaM. UlrichJ.D. HoltzmanD.M. Activated microglia mitigate Aβ-associated tau seeding and spreading.J. Exp. Med.20212188e2021054210.1084/jem.20210542 34100905
     [Google Scholar]
  89. LaurettiE. DincerO. PraticòD. Glycogen synthase kinase-3 signaling in Alzheimer’s disease.Biochim. Biophys. Acta Mol. Cell Res.20201867511866410.1016/j.bbamcr.2020.118664 32006534
     [Google Scholar]
  90. GiovinazzoD. BursacB. SbodioJ.I. NalluruS. VignaneT. SnowmanA.M. AlbacarysL.M. SedlakT.W. TorregrossaR. WhitemanM. FilipovicM.R. SnyderS.H. PaulB.D. Hydrogen sulfide is neuroprotective in Alzheimer’s disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation.Proc. Natl. Acad. Sci. 20211184e201722511810.1073/pnas.2017225118 33431651
     [Google Scholar]
  91. OzbenT. OzbenS. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease.Clin. Biochem.201972878910.1016/j.clinbiochem.2019.04.001 30954437
     [Google Scholar]
  92. ForloniG. BalducciC. Alzheimer’s disease, oligomers, and inflammation.J. Alzheimers Dis.20186231261127610.3233/JAD‑170819 29562537
     [Google Scholar]
  93. NewcombeE.A. Camats-PernaJ. SilvaM.L. ValmasN. HuatT.J. MedeirosR. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease.J. Neuroinflammation201815127610.1186/s12974‑018‑1313‑3 30249283
     [Google Scholar]
  94. NgA. TamW.W. ZhangM.W. HoC.S. HusainS.F. McIntyreR.S. HoR.C. IL-1β, IL-6, TNF- α and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta-Analysis.Sci. Rep.2018811205010.1038/s41598‑018‑30487‑6 30104698
     [Google Scholar]
  95. Al-KhayriJ.M. SahanaG.R. NagellaP. JosephB.V. AlessaF.M. Al-MssallemM.Q. Flavonoids as potential anti-inflammatory molecules: A review.Molecules2022279290110.3390/molecules27092901 35566252
     [Google Scholar]
  96. ZhangF. LiF. ChenG. Neuroprotective effect of apigenin in rats after contusive spinal cord injury.Neurol. Sci.201435458358810.1007/s10072‑013‑1566‑7 24166720
     [Google Scholar]
  97. ZhangT. SuJ. GuoB. WangK. LiX. LiangG. Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.Int. Immunopharmacol.2015281798710.1016/j.intimp.2015.05.024 26028151
     [Google Scholar]
  98. HostetlerG. RiedlK. CardenasH. Diosa-ToroM. ArangoD. SchwartzS. DoseffA.I. Flavone deglycosylation increases their anti‐inflammatory activity and absorption.Mol. Nutr. Food Res.201256455856910.1002/mnfr.201100596 22351119
     [Google Scholar]
  99. Rezai-ZadehK. EhrhartJ. BaiY. SanbergP.R. BickfordP. TanJ. ShytleR.D. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression.J. Neuroinflammation2008514110.1186/1742‑2094‑5‑41 18817573
     [Google Scholar]
  100. BugianiM. PlugB.C. ManJ.H.K. BreurM. van der KnaapM.S. Heterogeneity of white matter astrocytes in the human brain.Acta Neuropathol.2022143215917710.1007/s00401‑021‑02391‑3 34878591
     [Google Scholar]
  101. IoannouM.S. JacksonJ. SheuS.H. ChangC.L. WeigelA.V. LiuH. PasolliH.A. XuC.S. PangS. MatthiesD. HessH.F. Lippincott-SchwartzJ. LiuZ. Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity.Cell201917761522153510.1016/j.cell.2019.04.001
     [Google Scholar]
  102. AmaliaL. Glial Fibrillary Acidic Protein (GFAP): Neuroinflammation biomarker in acute ischemic stroke.J. Inflamm. Res.2021147501750610.2147/JIR.S342097 35002283
     [Google Scholar]
  103. LiangH. SonegoS. GyengesiE. RangelA. NiedermayerG. KarlT. MünchG. Anti-inflammatory and neuroprotective effect of apigenin: Studies in the gfap-il6 mouse model of chronic neuroinflammation.Free Radic. Biol. Med.2017108S1010.1016/j.freeradbiomed.2017.04.064
     [Google Scholar]
  104. CheD.N. ChoB.O. KimJ. ShinJ.Y. KangH.J. JangS.I. Effect of luteolin and apigenin on the production of Il-31 and Il-33 in lipopolysaccharides-activated microglia cells and their mechanism of action.Nutrients202012381110.3390/nu12030811 32204450
     [Google Scholar]
  105. Ionescu-TuckerA. CotmanC.W. Emerging roles of oxidative stress in brain aging and Alzheimer’s disease.Neurobiol. Aging2021107869510.1016/j.neurobiolaging.2021.07.014 34416493
     [Google Scholar]
  106. CalabreseV. CorneliusC. Dinkova-KostovaA.T. CalabreseE.J. MattsonM.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders.Antioxid. Redox Signal.201013111763181110.1089/ars.2009.3074 20446769
     [Google Scholar]
  107. JavedH. Mohamed FizurN.M. JhaN.K. AshrafG.M. OjhaS. Neuroprotective potential and underlying pharmacological mechanism of carvacrol for alzheimer’s and parkinson’s diseases.Curr. Neuropharmacol.20222161421 36567278
     [Google Scholar]
  108. BertholetA.M. DelerueT. MilletA.M. MoulisM.F. DavidC. DaloyauM. Arnauné-PelloquinL. DavezacN. MilsV. MiquelM.C. RojoM. BelenguerP. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity.Neurobiol. Dis.20169031910.1016/j.nbd.2015.10.011 26494254
     [Google Scholar]
  109. GiorgiC. MarchiS. PintonP. The machineries, regulation and cellular functions of mitochondrial calcium.Nat. Rev. Mol. Cell Biol.2018191171373010.1038/s41580‑018‑0052‑8 30143745
     [Google Scholar]
  110. ZhangB. PanC. FengC. YanC. YuY. ChenZ. GuoC. WangX. Role of mitochondrial reactive oxygen species in homeostasis regulation.Redox Rep.2022271455210.1080/13510002.2022.2046423 35213291
     [Google Scholar]
  111. YuH. LinX. WangD. ZhangZ. GuoY. RenX. XuB. YuanJ. LiuJ. SpencerP.S. WangJ.Z. YangX. Mitochondrial molecular abnormalities revealed by proteomic analysis of hippocampal organelles of mice triple transgenic for alzheimer disease.Front. Mol. Neurosci.2018117410.3389/fnmol.2018.00074 29593495
     [Google Scholar]
  112. GonzalezP. SabaterL. MathieuE. FallerP. HureauC. Why the ala-his-his peptide is an appropriate scaffold to remove and redox silence copper ions from the alzheimer’s-related Aβ peptide.Biomolecules20221210132710.3390/biom12101327 36291536
     [Google Scholar]
  113. WangD. YangY. ZouX. ZhangJ. ZhengZ. WangZ. Antioxidant apigenin relieves age-related muscle atrophy by inhibiting oxidative stress and hyperactive mitophagy and apoptosis in skeletal muscle of mice.J. Gerontol. A Biol. Sci. Med. Sci.202075112081208810.1093/gerona/glaa214 32857105
     [Google Scholar]
  114. ChirumboloS. Is mitochondria biogenesis and neuronal loss prevention in rat hippocampus promoted by apigenin?Basic Clin. Neurosci.201910654154410.32598/bcn.10.6.541 32477471
     [Google Scholar]
  115. SukhorukovV.S. MudzhiriN.M. VoronkovaA.S. BaranichT.I. GlinkinaV.V. IllarioshkinS.N. Mitochondrial disorders in alzheimer’s disease.Biochemistry202186666767910.1134/S0006297921060055 34225590
     [Google Scholar]
  116. OhY. AhnC.B. NamK.H. KimY.K. YoonN. JeJ.Y. Amino acid composition, antioxidant, and cytoprotective effect of blue mussel (mytilus edulis) hydrolysate through the inhibition of caspase-3 activation in oxidative stress-mediated endothelial cell injury.Mar. Drugs201917213510.3390/md17020135 30823522
     [Google Scholar]
  117. LinC.M. ChenC.T. LeeH.H. LinJ.K. Prevention of cellular ROS damage by isovitexin and related flavonoids.Planta Med.200268436536710.1055/s‑2002‑26753 11988866
     [Google Scholar]
  118. ÖzyürekM. BektaşoğluB. GüçlüK. ApakR. Measurement of xanthine oxidase inhibition activity of phenolics and flavonoids with a modified cupric reducing antioxidant capacity (CUPRAC) method.Anal. Chim. Acta20096361425010.1016/j.aca.2009.01.037 19231354
     [Google Scholar]
  119. HanJ.Y. AhnS.Y. KimC.S. YooS.K. KimS.K. KimH.C. HongJ.T. OhK.W. Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects.Biol. Pharm. Bull.20123591440144610.1248/bpb.b110686 22975493
     [Google Scholar]
  120. ChoiA.Y. ChoiJ.H. LeeJ.Y. YoonK.S. ChoeW. HaJ. YeoE.J. KangI. Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis.Neurochem. Int.201057214315210.1016/j.neuint.2010.05.006 20493918
     [Google Scholar]
  121. DouX. ZhouZ. RenR. XuM. Apigenin, flavonoid component isolated from Gentiana veitchiorum flower suppresses the oxidative stress through LDLR-LCAT signaling pathway.Biomed. Pharmacother.202012811029810.1016/j.biopha.2020.110298 32504920
     [Google Scholar]
  122. YangX. FangY. HouJ. WangX. LiJ. LiS. ZhengX. LiuY. ZhangZ. The heart as a target for deltamethrin toxicity: Inhibition of Nrf2/HO-1 pathway induces oxidative stress and results in inflammation and apoptosis.Chemosphere202230013447910.1016/j.chemosphere.2022.134479 35367492
     [Google Scholar]
  123. Perez-LealO. BarreroC.A. MeraliS. Pharmacological stimulation of nuclear factor (erythroid-derived 2)-like 2 translation activates antioxidant responses.J. Biol. Chem.201729234141081412110.1074/jbc.M116.770925 28684421
     [Google Scholar]
  124. LautrupS. SinclairD.A. MattsonM.P. FangE.F. NAD+ in brain aging and neurodegenerative disorders.Cell Metab.201930463065510.1016/j.cmet.2019.09.001 31577933
     [Google Scholar]
  125. MengH. YanW.Y. LeiY.H. WanZ. HouY.Y. SunL.K. ZhouJ.P. SIRT3 regulation of mitochondrial quality control in neurodegenerative diseases.Front. Aging Neurosci.20191131310.3389/fnagi.2019.00313 31780922
     [Google Scholar]
  126. Sidorova-DarmosE. SommerR. EubanksJ.H. The role of SIRT3 in the brain under physiological and pathological conditions.Front. Cell. Neurosci.20181219610.3389/fncel.2018.00196 30090057
     [Google Scholar]
  127. SatohA. ImaiS. GuarenteL. The brain, sirtuins, and ageing.Nat. Rev. Neurosci.201718636237410.1038/nrn.2017.42 28515492
     [Google Scholar]
  128. LeeJ. KimY. LiuT. HwangY.J. HyeonS.J. Im, H.; Lee, K.; Alvarez, V.E.; McKee, A.C.; Um, S.J.; Hur, M.; Mook-Jung, I.; Kowall, N.W.; Ryu, H. SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease.Aging Cell2018171e1267910.1111/acel.12679 29130578
     [Google Scholar]
  129. EscandeC. NinV. PriceN.L. CapelliniV. GomesA.P. BarbosaM.T. O’NeilL. WhiteT.A. SinclairD.A. ChiniE.N. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: Implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.Diabetes20136241084109310.2337/db12‑1139 23172919
     [Google Scholar]
  130. LiR.L. WangL.Y. DuanH.X. ZhangQ. GuoX. WuC. PengW. Regulation of mitochondrial dysfunction induced cell apoptosis is a potential therapeutic strategy for herbal medicine to treat neurodegenerative diseases.Front. Pharmacol.20221393728910.3389/fphar.2022.937289 36210852
     [Google Scholar]
  131. OnyangoI. BennettJ. StokinG. Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases.Neural Regen. Res.20211681467148210.4103/1673‑5374.303007 33433460
     [Google Scholar]
  132. Femi-AkinlosotuO.M. ShokunbiM.T. OlopadeF.E. IgbongP. Deficits of learning and spatial memory are associated with increased pyknosis of pyramidal neurons of the hippocampus of adult rats with chronic hydrocephalus.West Afr. J. Med.2021381110421049 34919360
     [Google Scholar]
  133. TaupinP. Apigenin and related compounds stimulate adult neurogenesis.Expert Opin. Ther. Pat.200919452352710.1517/13543770902721279 19441930
     [Google Scholar]
  134. DasM. DeviK.P. Dihydroactinidiolide regulates Nrf2/HO-1 expression and inhibits caspase-3/Bax pathway to protect SH-SY5Y human neuroblastoma cells from oxidative stress induced neuronal apoptosis.Neurotoxicology202184536310.1016/j.neuro.2021.02.006 33617922
     [Google Scholar]
  135. HaoQ. ChenJ. LuH. ZhouX. The ARTS of p53-dependent mitochondrial apoptosis.J. Mol. Cell Biol.2022 36565718
     [Google Scholar]
  136. ZhangY. YangX. GeX. ZhangF. Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice.Biomed. Pharmacother.201910972673310.1016/j.biopha.2018.10.161 30551525
     [Google Scholar]
  137. MoldoveanuT. CzabotarP.E. BAX, BAK, and BOK: A Coming of Age for the BCL-2 family effector proteins.Cold Spring Harb. Perspect. Biol.2020124a03631910.1101/cshperspect.a036319 31570337
     [Google Scholar]
  138. AsadiM. TaghizadehS. KavianiE. VakiliO. Taheri-AnganehM. TahamtanM. SavardashtakiA. Caspase‐3: Structure, function, and biotechnological aspects.Biotechnol. Appl. Biochem.20226941633164510.1002/bab.2233 34342377
     [Google Scholar]
  139. ZhengC. LiuS. ZhangX. HuY. ShangX. ZhuZ. HuangY. WuG. XiaoY. DuZ. LiangY. ChenD. ZangS. HuY. HeM. ZhangX. YuH. Shared genetic architecture between the two neurodegenerative diseases: Alzheimer’s disease and glaucoma.Front. Aging Neurosci.20221488057610.3389/fnagi.2022.880576 36118709
     [Google Scholar]
  140. KimA. NamY.J. LeeM.S. ShinY.K. SohnD.S. LeeC.S. Apigenin reduces proteasome inhibition-induced neuronal apoptosis by suppressing the cell death process.Neurochem. Res.201641112969298010.1007/s11064‑016‑2017‑7 27473386
     [Google Scholar]
  141. BalezR. SteinerN. EngelM. MuñozS.S. LumJ.S. WuY. WangD. VallottonP. SachdevP. O’ConnorM. SidhuK. MünchG. OoiL. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease.Sci. Rep.2016613145010.1038/srep31450 27514990
     [Google Scholar]
  142. ShengkaiD. QianqianL. YazhenS. The effects and regulatory mechanism of flavonoids from stems and leaves of scutellaria baicalensis georgi in promoting neurogenesis and improving memory impairment mediated by the BDNF-ERK-CREB signaling pathway in rats.CNS Neurol. Disord. Drug Targets202221435436610.2174/1871527320666210827112048 34455975
     [Google Scholar]
  143. ChiangN.N. LinT.H. TengY.S. SunY.C. ChangK.H. LinC.Y. Hsieh-LiH.M. SuM.T. ChenC.M. Lee-ChenG.J. Flavones 7,8-DHF, quercetin, and apigenin against tau toxicity via activation of TRKB signaling in ΔK280 TauRD-DsRed SH-SY5Y Cells.Front. Aging Neurosci.20211375889510.3389/fnagi.2021.758895 34975454
     [Google Scholar]
  144. OrcianiC. HallH. PentzR. ForetM.K. Do CarmoS. CuelloA.C. Long‐term nucleus basalis cholinergic depletion induces attentional deficits and impacts cortical neurons and BDNF levels without affecting the NGF synthesis.J. Neurochem.2022163214916710.1111/jnc.15683 35921478
     [Google Scholar]
  145. NguyenC.D. YooJ. HwangS.Y. ChoS.Y. KimM. JangH. NoK.O. ShinJ.C. KimJ.H. LeeG. Bee venom activates the Nrf2/HO-1 and TrkB/CREB/BDNF pathways in neuronal cell responses against oxidative stress induced by Aβ1-42.Int. J. Mol. Sci.2022233119310.3390/ijms23031193
     [Google Scholar]
  146. Lima GiacobboB. DoorduinJ. KleinH.C. DierckxR.A.J.O. BrombergE. de VriesE.F.J. Brain-derived neurotrophic factor in brain disorders: Focus on neuroinflammation.Mol. Neurobiol.20195653295331210.1007/s12035‑018‑1283‑6 30117106
     [Google Scholar]
  147. PatilS.P. JainP.D. SanchetiJ.S. GhumatkarP.J. TambeR. SathayeS. RETRACTED: Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice.Neuropharmacology20148619220210.1016/j.neuropharm.2014.07.012 25087727
     [Google Scholar]
  148. WengL. GuoX. LiY. YangX. HanY. Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice.Eur. J. Pharmacol.2016774505410.1016/j.ejphar.2016.01.015 26826594
     [Google Scholar]
  149. AnushaC. SumathiT. JosephL.D. Protective role of apigenin on rotenone induced rat model of Parkinson’s disease: Suppression of neuroinflammation and oxidative stress mediated apoptosis.Chem. Biol. Interact.2017269677910.1016/j.cbi.2017.03.016 28389404
     [Google Scholar]
  150. ChenZ. WuM. LaiQ. ZhouW. WenX. YinX. Epigenetic regulation of synaptic disorder in Alzheimer’s disease.Front. Neurosci.20221688801410.3389/fnins.2022.888014 35992921
     [Google Scholar]
  151. TziorasM. McGeachanR.I. DurrantC.S. Spires-JonesT.L. Synaptic degeneration in Alzheimer disease.Nat. Rev. Neurol.2023191193810.1038/s41582‑022‑00749‑z 36513730
     [Google Scholar]
  152. SkaperS.D. FacciL. ZussoM. GiustiP. Synaptic plasticity, dementia and alzheimer disease.CNS Neurol. Disord. Drug Targets201716322023310.2174/1871527316666170113120853 28088900
     [Google Scholar]
  153. RocchiA. SacchettiS. De FuscoA. GiovediS. ParisiB. CescaF. HöltjeM. RuprechtK. Ahnert-HilgerG. BenfenatiF. Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function.Cell Death Dis.2019101186410.1038/s41419‑019‑2106‑z 31727880
     [Google Scholar]
  154. CalabreseV. MancusoC. CalvaniM. RizzarelliE. ButterfieldD.A. Giuffrida StellaA.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity.Nat. Rev. Neurosci.200781076677510.1038/nrn2214 17882254
     [Google Scholar]
  155. TuF. PangQ. HuangT. ZhaoY. LiuM. ChenX. Apigenin ameliorates post-stroke cognitive deficits in rats through histone acetylation-mediated neurochemical alterations.Med. Sci. Monit.2017234004401310.12659/MSM.902770 28821706
     [Google Scholar]
  156. MahatoP.K. RamsakhaN. OjhaP. GuliaR. SharmaR. BhattacharyyaS. GroupI. Group I metabotropic glutamate receptors (mGluRs): Ins and outs.Adv. Exp. Med. Biol.2018111216317510.1007/978‑981‑13‑3065‑0_12 30637697
     [Google Scholar]
  157. WangR. ReddyP.H. Role of glutamate and NMDA receptors in alzheimer’s disease.J. Alzheimers Dis.20175741041104810.3233/JAD‑160763 27662322
     [Google Scholar]
  158. ReglodiD. TamasA. JunglingA. VaczyA. RivnyakA. FulopB.D. SzaboE. LubicsA. AtlaszT. Protective effects of pituitary adenylate cyclase activating polypeptide against neurotoxic agents.Neurotoxicology20186618519410.1016/j.neuro.2018.03.010 29604313
     [Google Scholar]
  159. ChangC.Y. LinT.Y. LuC.W. WangC.C. WangY.C. ChouS.S.P. WangS.J. Apigenin, a natural flavonoid, inhibits glutamate release in the rat hippocampus.Eur. J. Pharmacol.2015762728110.1016/j.ejphar.2015.05.035 26007643
     [Google Scholar]
  160. BurnsA.M. GräffJ. Cognitive epigenetic priming: leveraging histone acetylation for memory amelioration.Curr. Opin. Neurobiol.202167758410.1016/j.conb.2020.08.011 33120188
     [Google Scholar]
  161. VillainH. FlorianC. RoulletP. HDAC inhibition promotes both initial consolidation and reconsolidation of spatial memory in mice.Sci. Rep.2016612701510.1038/srep27015 27270584
     [Google Scholar]
  162. HyndmanK.A. KnepperM.A. Dynamic regulation of lysine acetylation: The balance between acetyltransferase and deacetylase activities.Am. J. Physiol. Renal Physiol.20173134F842F84610.1152/ajprenal.00313.2017 28701313
     [Google Scholar]
  163. DagnasM. MicheauJ. DecorteL. BeracocheaD. MonsN. Post‐training, intrahippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice.Hippocampus201525782783710.1002/hipo.22406 25530477
     [Google Scholar]
  164. McAlpinB.R. MahalingamR. SinghA.K. DharmarajS. ChrisikosT.T. BoukelmouneN. KavelaarsA. HeijnenC.J. HDAC6 inhibition reverses long-term doxorubicin-induced cognitive dysfunction by restoring microglia homeostasis and synaptic integrity.Theranostics202212260361910.7150/thno.67410 34976203
     [Google Scholar]
  165. PandeyM. KaurP. ShuklaS. AbbasA. FuP. GuptaS. Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: In Vitro and In Vivo study.Mol. Carcinog.2012511295296210.1002/mc.20866 22006862
     [Google Scholar]
  166. de LeoG. GulinoR. CoradazziM. LeanzaG. Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory.Brain Commun.202251fcac33810.1093/braincomms/fcac338 36632183
     [Google Scholar]
  167. AndradeS. RamalhoM.J. PereiraM.C. LoureiroJ.A. Resveratrol brain delivery for neurological disorders prevention and treatment.Front. Pharmacol.20189126110.3389/fphar.2018.01261 30524273
     [Google Scholar]
  168. Ben-AzuB. AderibigbeA.O. AjayiA.M. UmukoroS. IwalewaE.O. Involvement of L ‐arginine‐nitric oxide pathway in the antidepressant and memory promoting effects of morin in mice.Drug Dev. Res.20198081071107910.1002/ddr.21588 31407363
     [Google Scholar]
  169. LeeS.Y. LeeS.J. HanC. PatkarA.A. MasandP.S. PaeC.U. Oxidative/nitrosative stress and antidepressants: Targets for novel antidepressants.Prog. Neuropsychopharmacol. Biol. Psychiatry20134622423510.1016/j.pnpbp.2012.09.008 23022673
     [Google Scholar]
  170. Concetta ScutoM. MancusoC. TomaselloB. Laura OntarioM. CavallaroA. FrascaF. MaiolinoL. Trovato SalinaroA. CalabreseE.J. CalabreseV. Curcumin, hormesis and the nervous system.Nutrients20191110241710.3390/nu11102417 31658697
     [Google Scholar]
  171. SeneviratneU. NottA. BhatV.B. RavindraK.C. WishnokJ.S. TsaiL.H. TannenbaumS.R. S -nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration.Proc. Natl. Acad. Sci. 2016113154152415710.1073/pnas.1521318113 27035958
     [Google Scholar]
  172. SinghS. Updates on versatile role of putative gasotransmitter nitric oxide: Culprit in neurodegenerative disease pathology.ACS Chem. Neurosci.202011162407241510.1021/acschemneuro.0c00230 32564594
     [Google Scholar]
  173. ChoiJ.S. Nurul IslamM. Yousof AliM. KimE.J. KimY.M. JungH.A. Effects of C-glycosylation on anti-diabetic, anti-Alzheimer’s disease and anti-inflammatory potential of apigenin.Food Chem. Toxicol.201464273310.1016/j.fct.2013.11.020 24291393
     [Google Scholar]
  174. YangY. BaiL. LiX. XiongJ. XuP. GuoC. XueM. Transport of active flavonoids, based on cytotoxicity and lipophilicity: An evaluation using the blood-brain barrier cell and Caco-2 cell models.Toxicol. In Vitro201428338839610.1016/j.tiv.2013.12.002 24362044
     [Google Scholar]
  175. AliF. Rahul; Naz, F.; Jyoti, S.; Siddique, Y.H. Health functionality of apigenin: A review.Int. J. Food Prop.20172061197123810.1080/10942912.2016.1207188
     [Google Scholar]
  176. LothaR. SivasubramanianA. Flavonoids nutraceuticals in prevention and treatment of cancer: A review.Asian J. Pharm. Clin. Res.2018111424710.22159/ajpcr.2018.v11i1.23410
     [Google Scholar]
  177. BanerjeeK. BanerjeeS. DasS. MandalM. Probing the potential of apigenin liposomes in enhancing bacterial membrane perturbation and integrity loss.J. Colloid Interface Sci.2015453485910.1016/j.jcis.2015.04.030 25965432
     [Google Scholar]
  178. RossJ.A. KasumC.M. Dietary flavonoids: Bioavailability, metabolic effects, and safety.Annu. Rev. Nutr.2002221193410.1146/annurev.nutr.22.111401.144957 12055336
     [Google Scholar]
  179. SinghP. MishraS.K. NoelS. SharmaS. RathS.K. Acute exposure of apigenin induces hepatotoxicity in Swiss mice.PLoS One201272e3196410.1371/journal.pone.0031964 22359648
     [Google Scholar]
  180. TangD. ChenK. HuangL. LiJ. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone.Expert Opin. Drug Metab. Toxicol.201713332333010.1080/17425255.2017.1251903 27766890
     [Google Scholar]
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Efficacy and Safety of Natural Apigenin Treatment for Alzheimer's Disease: Focus on In vivo Research Advancements
Curr. Neuropharmacol. 23, 728 (2025); https://doi.org/10.2174/1570159X23666241211095018
/content/journals/cn/10.2174/1570159X23666241211095018
/content/journals/cn/10.2174/1570159X23666241211095018
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  • Article Type:     Research Article
Keyword(s): Alzheimer's disease; apigenin; apigenin treatment; meta-analysis; pharmacological mechanism; systematic review

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