细胞代谢组学在阿尔茨海默病药物研究中的应用

曹秀瑜; 金梦颍; 沈淑琦; 王辉; 洪战英; 曹秀瑜; 金梦颍; 沈淑琦; 王辉; 洪战英

doi:10.12206/j.issn.2097-2024.202509026

[1]

AARSLAND D, SUNDE A L, TOVAR-RIOS D A, et al. Prevalence of Alzheimer’s disease’s pathology in the community[J]. Nature, 2025: 1-5.

[2]

徐勇, 王军, 王虹峥, 等. 2023中国阿尔茨海默病数据与防控策略[J]. 阿尔茨海默病及相关病, 2023, 6(3): 175-192.

[3]

VAN GIAU V, BAGYINSZKY E, YANG Y S, et al. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing[J]. Sci Rep, 2019, 9(1): 8368. doi: 10.1038/s41598-019-44848-2

[4]

CONTI FILHO C E, LOSS L B, MARCOLONGO-PEREIRA C, et al. Advances in Alzheimer’s disease’s pharmacological treatment[J]. Front Pharmacol, 2023, 14: 1101452. doi: 10.3389/fphar.2023.1101452

[5]

BUDD HAEBERLEIN S, AISEN P S, BARKHOF F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease[J]. J Prev Alzheimers Dis, 2022, 9(2): 197-210. doi: 10.14283/jpad.2022.30

[6]

VAN DYCK C H, SWANSON C J, AISEN P, et al. Lecanemab in early Alzheimer’s disease’s[J]. N. Engl. J. Med., 2023, 388(1): 9-21. doi: 10.1056/NEJMoa2212948

[7]

CHEN S Y, GAO Y, SUN J Y, et al. Traditional Chinese medicine: role in reducing β-amyloid, apoptosis, autophagy, neuroinflammation, oxidative stress, and mitochondrial dysfunction of Alzheimer’s disease[J]. Front Pharmacol, 2020, 11: 497. doi: 10.3389/fphar.2020.00497

[8]

戴建英, 王辉, 刘敏, 等. 阿尔茨海默病的病理模型及代谢组学研究进展[J]. 药学服务与研究, 2021, 21(4): 241-247,320.

[9]

CHEN Z R, HUANG J B, YANG S L, et al. Role of cholinergic signaling in Alzheimer’s disease[J]. Molecules, 2022, 27(6): 1816. doi: 10.3390/molecules27061816

[10]

金艳, 李阳, 雷旭伟. 多奈哌齐治疗AD源性轻度认知功能障碍患者的临床研究[J]. 中国临床药理学杂志, 2024, 40(18): 2616-2620. doi: 10.13699/j.cnki.1001-6821.2024.18.002

[11]

YEAPURI P, MACHHI J, LU Y M, et al. Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice[J]. Mol Neurodegener, 2023, 18(1): 97. doi: 10.1186/s13024-023-00692-7

[12]

SÖDERBERG L, JOHANNESSON M, NYGREN P, et al. Lecanemab, aducanumab, and gantenerumab: binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease[J]. Neurotherapeutics, 2023, 20(1): 195-206. doi: 10.1007/s13311-022-01308-6

[13]

ZHANG X, CAO R L, ZHU C, et al. Mechanism of anti-AD action of OAB-14 by enhancing the function of glymphatic system[J]. Neurochem Int, 2023, 171: 105633. doi: 10.1016/j.neuint.2023.105633

[14]

MURALIDAR S, AMBI S V, SEKARAN S, et al. Role of tau protein in Alzheimer’s disease: The prime pathological player[J]. Int J Biol Macromol, 2020, 163: 1599-1617. doi: 10.1016/j.ijbiomac.2020.07.327

[15]

GAUTHIER S, FELDMAN H H, SCHNEIDER L S, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial[J]. Lancet, 2016, 388(10062): 2873-2884. doi: 10.1016/S0140-6736(16)31275-2

[16]

WISCHIK C M, STAFF R T, WISCHIK D J, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease[J]. J Alzheimers Dis, 2015, 44(2): 705-720. doi: 10.3233/jad-142874

[17]

NOVAK P, SCHMIDT R, KONTSEKOVA E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial[J]. Lancet Neurol, 2017, 16(2): 123-134. doi: 10.1016/S1474-4422(16)30331-3

[18]

杨淑达, 于浩飞, 张兰春, 等. 人参皂苷Rb1对Aβ1-42导致的Tau蛋白异常磷酸化的影响[J]. 天然产物研究与开发, 2020(7): 1143-1147,1098. doi: 10.16333/j.1001-6880.2020.7.008

[19]

ROVETA F, BONINO L, PIELLA E M, et al. Neuroinflammatory biomarkers in Alzheimer’s disease: from pathophysiology to clinical implications[J]. Int J Mol Sci, 2024, 25(22): 11941. doi: 10.3390/ijms252211941

[20]

DHAPOLA R, HOTA S S, SARMA P, et al. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer’s disease[J]. Inflammopharmacology, 2021, 29(6): 1669-1681. doi: 10.1007/s10787-021-00889-6

[21]

KONG F G, JIANG X, WANG R C, et al. Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease[J]. J Neuroinflammation, 2020, 17(1): 305. doi: 10.1186/s12974-020-01967-2

[22]

HE Y, WANG Y M, LIU S, et al. A metabolomic study of the urine of rats with Alzheimer’s disease and the efficacy of Ding-Zhi-Xiao-Wan on the afflicted rats[J]. J Sep Sci, 2020, 43(8): 1458-1465. doi: 10.1002/jssc.201900944

[23]

WANG H, CHAO L, SHEN S Q, et al. Exploring the pharmacological mechanism of Bu-Wang San on Alzheimer’s disease through multiple GEO datasets of the human hippocampus, network pharmacology, and metabolomics based on GC-MS and UPLC-Q/TOF-MS[J]. J Ethnopharmacol, 2025, 350: 119994. doi: 10.1016/j.jep.2025.119994

[24]

管秀菊, 侯翰如, 张立娟, 等. 人参-石菖蒲药对防治阿尔茨海默病的作用机制及临床应用[J]. 中医药导报, 2020, 26(12): 161-163,190. doi: 10.13862/j.cnki.cn43-1446/r.2020.12.040

[25]

范宇婷, 刘志强, 邢俊鹏, 等. 基于空间代谢组学方法研究人参治疗阿尔兹海默症大鼠的药效物质及作用机制[J]. 质谱学报, 2024, 45(6): 723-738.

[26]

STOCKWELL B R, FRIEDMANN ANGELI J P, BAYIR H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell, 2017, 171(2): 273-285. doi: 10.1016/j.cell.2017.09.021

[27]

XIONG R, LIU H X, ZHANG S P, et al. Acorus tatarinowii Schott attenuates Alzheimer’s disease via neuronal ferroptosis inhibition: a synergistic network pharmacology and multi-omics profiling study[J]. J Ethnopharmacol, 2026, 356: 120829. doi: 10.1016/j.jep.2025.120829

[28]

ZHAO C M, YUE J, XIE Y, et al. A ginsenoside composition ameliorated aβ and tau aggregation via autophagy lysosome pathway[J]. Mol Neurobiol, 2025, 62(9): 11822-11833. doi: 10.1007/s12035-025-05017-x

[29]

JAKARIA M, AZAM S, GO E A, et al. Biological evidence of gintonin efficacy in memory disorders[J]. Pharmacol Res, 2021, 163: 105221. doi: 10.1016/j.phrs.2020.105221

[30]

JANG M, CHOI S H, CHOI J H, et al. Ginseng gintonin attenuates the disruptions of brain microvascular permeability and microvascular endothelium junctional proteins in an APPswe/PSEN-1 double-transgenic mouse model of Αlzheimer’s disease[J]. Exp Ther Med, 2021, 21(4): 310. doi: 10.3892/etm.2021.9741

[31]

SAKI G, EIDI A, MORTAZAVI P, et al. Effect of β-asarone in normal and β-amyloid-induced Alzheimeric rats[J]. Arch Med Sci, 2020, 16(3): 699-706. doi: 10.5114/aoms.2020.94659

[32]

肖艮, 刘静. 茯苓酸调节HMGB1/TLR4信号通路对阿尔兹海默病大鼠神经炎症的影响[J]. 河北医药, 2025, 47(8): 1243-1247.

[33]

MU P P, LIU Y T, JIANG S M, et al. Glial cell line-derived neurotrophic factor alters lipid composition and protein distribution in MPP+-injured differentiated SH-SY5Y cells[J]. J Cell Physiol, 2020, 235(12): 9347-9360. doi: 10.1002/jcp.29738

[34]

LISTA S, GONZÁLEZ-DOMÍNGUEZ R, LÓPEZ-ORTIZ S, et al. Integrative metabolomics science in Alzheimer’s disease: Relevance and future perspectives[J]. Ageing Res Rev, 2023, 89: 101987. doi: 10.1016/j.arr.2023.101987

[35]

BHATTI J S, KHULLAR N, MISHRA J, et al. Stem cells in the treatment of Alzheimer’s disease–Promises and pitfalls[J]. Biochim Biophys Acta BBA Mol Basis Dis, 2023, 1869(6): 166712.

[36]

RAO A, CHEN N, KIM M J, et al. Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model[J]. Cell Stem Cell, 2025, 32(1): 86-104. e7.

[37]

OYEBODE O D, TULAY P. Mesenchymal stem cells applications in Alzheimer’s disease[J]. Glob Med Genet, 2023, 10(4): 382-387. doi: 10.1055/s-0043-1777087

[38]

GIOVANNELLI L, BARI E, JOMMI C, et al. Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access[J]. Bioact Mater, 2023, 29: 16-35. doi: 10.1016/j.bioactmat.2023.06.013

[39]

LIU S, FAN M, XU J X, et al. Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology[J]. J Neuroinflammation, 2022, 19(1): 35. doi: 10.1186/s12974-022-02393-2

[40]

HONG C G, CHEN M L, DUAN R, et al. Transplantation of nasal olfactory mucosa mesenchymal stem cells benefits Alzheimer’s disease[J]. Mol Neurobiol, 2022, 59(12): 7323-7336. doi: 10.1007/s12035-022-03044-6

[41]

YU X J, LI Y C, MU X H. Effect of quercetin on PC12 Alzheimer’s disease cell model induced by aβ(25-35)and its mechanism based on Sirtuin1/Nrf2/HO-1 pathway[J]. Biomed Res Int, 2020, 2020: 8210578. doi: 10.1155/2020/8210578

[42]

BELL M, ZEMPEL H. SH-SY5Y-derived neurons: a human neuronal model system for investigating TAU sorting and neuronal subtype-specific TAU vulnerability[J]. Rev Neurosci, 2021, 33(1): 1-15. doi: 10.20944/preprints202006.0203.v2

[43]

ROYTRAKUL S, JARESITTHIKUNCHAI J, PHAONAKROP N, et al. Secretomic changes of amyloid beta peptides on Alzheimer’s disease related proteins in differentiated human SH-SY5Y neuroblastoma cells[J]. PeerJ, 2024, 12: e17732. doi: 10.7717/peerj.17732

[44]

YANAKIEV M, SOPER O, BERG D A, et al. Modelling Alzheimer’s disease using human brain organoids: current progress and challenges[J]. Expert Rev Mol Med, 2022, 25: e3. doi: 10.1017/erm.2022.40

[45]

CHEN X W, SUN G Q, TIAN E, et al. Modeling sporadic Alzheimer’s disease in human brain organoids under serum exposure[J]. Adv Sci, 2021, 8(18): 2101462. doi: 10.1002/advs.202101462

[46]

ZHANG Y B, TANG C, HE Y, et al. Semaglutide ameliorates Alzheimer’s disease and restores oxytocin in APP/PS1 mice and human brain organoid models[J]. Biomed Pharmacother, 2024, 180: 117540. doi: 10.1016/j.biopha.2024.117540

[47]

BHARDWAJ S, KESARI K K, RACHAMALLA M, et al. CRISPR/Cas9 gene editing: New hope for Alzheimer’s disease therapeutics[J]. J Adv Res, 2022, 40: 207-221. doi: 10.1016/j.jare.2021.07.001

[48]

FERNANDES T, MELO T, CONDE T, et al. Mapping the lipidome in mitochondria-associated membranes(MAMs)in an in vitro model of Alzheimer’s disease[J]. J Neurochem, 2024, 168(7): 1237-1253.

[49]

XIONG X M, LI S J, HAN T L, et al. Study of mitophagy and ATP-related metabolomics based on β-amyloid levels in Alzheimer’s disease[J]. Exp Cell Res, 2020, 396(1): 112266. doi: 10.1016/j.yexcr.2020.112266

[50]

TRAXLER L, HERDY J R, STEFANONI D, et al. Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease[J]. Cell Metab, 2022, 34(9): 1248-1263. e6.

[51]

王辉, 蔡颖, 刘敏, 等. 基于UHPLC-QTOF/MS的细胞代谢组学对丹参和知母防治阿尔茨海默病的药效比较研究[J]. 药学学报, 2021, 56(9): 2394-2402. doi: 10.16438/j.0513-4870.2021-0646

[52]

JUNG E S, CHOI H, MOOK-JUNG I. Decoding microglial immunometabolism: a new frontier in Alzheimer’s disease research[J]. Mol Neurodegener, 2025, 20(1): 37. doi: 10.1186/s13024-025-00825-0

[53]

QIU Y G, HOU Y, WETZEL L, et al. Cell type-specific master metabolic regulators of Alzheimer’s disease[J]. bioRxiv, 2025. DOI: 10.1101/2025.07.11.664443.

[54]

ISAAC A, STAN L, HUSSEIN N, Y. Uncovering mechanisms of brain inflammation in Alzheimer’s disease with APOE4: application of single cell-type lipidomics[J]. Ann N Y Acad Sci, 2022, 1518(1): 84-105. doi: 10.1111/nyas.14907

[55]

ASADIAN M, CROSLOW S W, TRINKLEIN T J, et al. High-throughput fluorescence-guided sequential single-cell MALDI-ICC mass spectrometry[J]. Anal Chem, 2025, 97(29): 15864-15872. doi: 10.1021/acs.analchem.5c02092

[56]

CHEN Y W, HU D J, ZHAO L S, et al. Unraveling metabolic alterations in transgenic mouse model of Alzheimer’s disease using MALDI MS imaging with 4-aminocinnoline-3-carboxamide matrix[J]. Anal Chim Acta, 2022, 1192: 339337. doi: 10.1016/j.aca.2021.339337

[57]

CAIRNS J L, HUBER J, LEWEN A, et al. Mass-guided single-cell MALDI imaging of low-mass metabolites reveals cellular activation markers[J]. Adv Sci, 2025, 12(5): 2410506. doi: 10.1002/advs.202410506