蛋白质酶促糖基化修饰在阿尔茨海默病中的研究进展

doi:10.3969/j.issn.1003-9198.2025.06.020

摘要/Abstract

摘要： AD是一种进行性发展的神经系统退行性疾病,其临床特征包括不同程度的认知功能障碍和生活自理能力下降,还可伴随精神行为异常。随着年龄的增长,AD的发病率不断上升。蛋白质酶促糖基化修饰是蛋白质翻译后修饰的重要形式,在AD的发生发展中扮演了重要角色,N-糖基化修饰、O-糖基化修饰与AD之间具有密切的相关性。本综述为进一步明确AD的发病机制、探寻早期诊断方法和新型有效治疗手段提供参考。

关键词: 蛋白质酶促糖基化, 翻译后修饰, 阿尔茨海默病

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive function and self-care ability, often accompanied by mental and behavioral abnormalities. The incidence of AD increases with age. Enzymatic protein glycosylation, a critical post-translational modification, plays a significant role in the development of AD, and N-linked glycosylation and O-linked glycosylation are closely associated with the development of AD. This review provides insights into the underlying pathogenesis, as well as to explore potential early diagnostic approaches and novel therapeutic strategies.

Key words: enzymatic protein glycosylation, post-translational modifications, Alzheimer’s disease

中图分类号:

R749.13

顾星月, 高伟, 鲁翔. 蛋白质酶促糖基化修饰在阿尔茨海默病中的研究进展[J]. 实用老年医学, 2025, 39(6): 631-635.

GU Xingyue, GAO Wei, LU Xiang. Advances in the study of enzymatic protein glycosylation in Alzheimer’s disease[J]. Practical Geriatrics, 2025, 39(6): 631-635.

参考文献

[1] KNOPMAN D S, AMIEVA H, PETERSEN R C, et al. Alzheimer disease[J]. Nat Rev Dis Primers, 2021, 7(1): 33.
[2] 首都医科大学宣武医院国家神经疾病医学中心, 中国疾病预防控制中心慢性非传染性疾病预防控制中心, 国家卫生健康委能力建设和继续教育中心, 等. 中国阿尔茨海默病蓝皮书(精简版)[J]. 中华医学杂志, 2024, 104(29): 2701-2727.
[3] LIN T, VAN HUSEN L S, YU Y, et al. Lack of N-glycosylation increases amyloidogenic processing of the amyloid precursor protein[J]. Glycobiology, 2022, 32(6): 506-517.
[4] PATON B, SUAREZ M, HERRERO P, et al. Glycosylation biomarkers associated with age-related diseases and current methods for glycan analysis[J]. Int J Mol Sci, 2021, 22(11): 5788.
[5] ZHOU R Z, DUELL F, AXENHUS M, et al. A glycan biomarker predicts cognitive decline in amyloid- and tau-negative patients[J]. Brain Commun, 2024, 6(6): fcae371.
[6] ZHOU R Z, VETRANO D L, GRANDE G, et al. A glycan epitope correlates with tau in serum and predicts progression to Alzheimer’s disease in combination with APOE4 allele status[J]. Alzheimers Dement, 2023, 19(7): 3244-3249.
[7] CHEN Z, YU Q, YU Q, et al. In-depth site-specific analysis of N-glycoproteome in human cerebrospinal fluid and glycosylation landscape changes in Alzheimer’s disease[J]. Mol Cell Proteomics, 2021, 20: 100081.
[8] HOSHI K, ITO H, ABE E, et al. Transferrin biosynthesized in the brain is a novel biomarker for Alzheimer’s disease[J]. Metabolites, 2021, 11(9): 616.
[9] LOSEV Y, FRENKEL-PINTER M, ABU-HUSSIEN M, et al. Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration[J]. Cell Mol Life Sci, 2021, 78(5): 2231-2245.
[10] ZHANG X, YUAN H, LYU J, et al. Association of dementia with immunoglobulin G N-glycans in a Chinese Han population[J]. NPJ Aging Mech Dis, 2021, 7(1): 3.
[11] WANG Y, CAO Y, HUANG H, et al. DHEC mesylate attenuates pathologies and aberrant bisecting N-glycosylation in Alzheimer’s disease models[J]. Neuropharmacology, 2024, 248: 109863.
[12] WANG Y, DU Y, HUANG H, et al. Targeting aberrant glycosylation to modulate microglial response and improve cognition in models of Alzheimer’s disease[J]. Pharmacol Res, 2024, 202: 107133.
[13] HAUKEDAL H, FREUDE K K. Implications of glycosylation in Alzheimer’s disease[J]. Front Neurosci, 2021, 14: 625348.
[14] KRONIMUS Y, ALBUS A, HASENBERG M, et al. Fc N-glycosylation of autoreactive Aβ antibodies as a blood-based biomarker for Alzheimer’s disease[J]. Alzheimers Dement, 2023, 19(12): 5563-5572.
[15] CHEN Z, WANG D, YU Q, et al. In-depth site-specific O-glycosylation analysis of glycoproteins and endogenous peptides in cerebrospinal fluid (CSF) from healthy individuals, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) patients[J]. ACS Chem Biol, 2022, 17(11): 3059-3068.
[16] SINGH Y, REGMI D, ORMAZA D, et al. Mucin-type O-glycosylation proximal to β-secretase cleavage site affects APP processing and aggregation fate[J]. Front Chem, 2022, 10: 859822.
[17] TACHIDA Y, IIJIMA J, TAKAHASHI K, et al. O-GalNAc glycosylation determines intracellular trafficking of APP and Aβ production[J]. J Biol Chem, 2023, 299(7): 104905.
[18] AKASAKA-MANYA K, MANYA H. The role of APP O-glycosylation in Alzheimer’s disease[J]. Biomolecules, 2020, 10(11): 1569.
[19] LEE B E, SUH P G, KIM J I. O-GlcNAcylation in health and neurodegenerative diseases[J]. Exp Mol Med, 2021, 53(11): 1674-1682.
[20] GRIFFITH L S, MATHES M, SCHMITZ B. β-Amyloid precursor protein is modified with O-linked N-acetylglucosamine[J]. J Neurosci Res, 1995, 41(2): 270-278.
[21] CHUN Y S, PARK Y, OH H G, et al. O-GlcNAcylation promotes non-amyloidogenic processing of amyloid-β protein precursor via inhibition of endocytosis from the plasma membrane[J]. J Alzheimers Dis, 2015, 44(1): 261-275.
[22] PARK J, HA H J, CHUNG E S, et al. O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis[J]. Sci Adv, 2021, 7(3): eabd3207.
[23] BALANA A T, LEVINE P M, CRAVEN T W, et al. O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity[J]. Nat Chem, 2021, 13(5): 441-450.
[24] CANTRELLE F X, LOYENS A, TRIVELLI X, et al. Phosphorylation and O-GlcNAcylation of the PHF-1 epitope of tau protein induce local conformational changes of the C-terminus and modulate tau self-assembly into fibrillar aggregates[J]. Front Mol Neurosci, 2021, 14: 661368.
[25] ROSTGAARD N, JUL P H, GARMER M, et al. Increasing O-GlcNAcylation attenuates tau hyperphosphorylation and behavioral impairment in rTg4510 tauopathy mice[J]. J Integr Neurosci, 2023, 22(5): 135.
[26] PAN D, GU J H, ZHANG J, et al. Thiamme2-G, a novel O-GlcNAcase inhibitor, reduces tau hyperphosphorylation and rescues cognitive impairment in mice[J]. J Alzheimers Dis, 2021, 81(1): 273-286.
[27] LI X, HAN J, BUJARANIPALLI S, et al. Structure-based discovery and development of novel O-GlcNAcase inhibitors for the treatment of Alzheimer’s disease[J]. Eur J Med Chem, 2022, 238: 114444.
[28] WEBER P, MÉSZÁROS Z, JAGEČIĆ D, et al. Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer’s disease[J]. Chem Commun, 2022, 58(63): 8838-8841.
[29] WEBER P, BOJAROVÁ P, BROUZDOVÁ J, et al. Diaminocyclopentane-l-lysine adducts: potent and selective inhibitors of human O-GlcNAcase[J]. Bioorg Chem, 2024, 148: 107452.
[30] ALTEEN M G, TAN H Y, VOCADLO D J. Monitoring and modulating O-GlcNAcylation: assays and inhibitors of O-GlcNAc processing enzymes[J]. Curr Opin Struct Biol, 2021, 68: 157-165.