切换至 "中华医学电子期刊资源库"

中华临床医师杂志(电子版) ›› 2021, Vol. 15 ›› Issue (03) : 224 -228. doi: 10.3877/cma.j.issn.1674-0785.2021.03.014

综述

阿尔兹海默病发病机制的新进展
苏霄1, 赵世刚1,(), 赵婷婷1, 岳晓蓉1   
  1. 1. 010050 呼和浩特,内蒙古医科大学附属医院神经内科
  • 收稿日期:2020-08-25 出版日期:2021-03-15
  • 通信作者: 赵世刚

New advances in understanding of pathogenesis of Alzheimer's disease

Xiao Su1, Shigang Zhao1,(), Tingting Zhao1, Xiaorong Yue1   

  1. 1. Department of Neurology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
  • Received:2020-08-25 Published:2021-03-15
  • Corresponding author: Shigang Zhao
引用本文:

苏霄, 赵世刚, 赵婷婷, 岳晓蓉. 阿尔兹海默病发病机制的新进展[J/OL]. 中华临床医师杂志(电子版), 2021, 15(03): 224-228.

Xiao Su, Shigang Zhao, Tingting Zhao, Xiaorong Yue. New advances in understanding of pathogenesis of Alzheimer's disease[J/OL]. Chinese Journal of Clinicians(Electronic Edition), 2021, 15(03): 224-228.

阿尔兹海默病(AD)是一种常见的神经系统退行性病变,也是造成老年痴呆最常见的病因之一,其在全球范围内的发病率逐年增高,然而几乎所有针对经典发病机制的药物都未取得令人满意的临床效果。这使得科学家逐渐从简单的淀粉样蛋白假说转向新的发病机制理论,包括伽玛振荡、朊病毒样传播、脑血管收缩、生长激素促分泌素受体1α通路的作用、微生物感染、炎症消散障碍。本文论述了相关进展,以期对AD的发病机制和未来治疗策略提供参考。

Alzheimer's disease (AD) is a common neurodegenerative disease and one of the most common causes of senile dementia. The incidence rate of AD is increasing year by year globally, however, almost all the drugs targeting the classic pathogenesis have not achieved satisfactory clinical results. This has led scientists to gradually shift from the simple amyloid hypothesis to new pathogenesis theories, including gamma oscillation, prion-like transmission, cerebral vasoconstriction, the role of the growth hormone secretagogue receptor 1α (GHSR1α) pathway, microbial infection, and dissipation of inflammation disorder. This article reviews the progress in the understanding of the pathogenesis of AD and provides a perspective on future treatment strategies.

1
Coronel R, Bernabeu-Zornoza A, Palmer C, et al. Role of amyloid precursor protein (APP) and its derivatives in the biology and cell fate specification of neural stem cells [J]. Mol Neurobiol, 2018, 55(9): 7107.
2
Di Carlo M, Giacomazza D, San Biagio PL. Alzheimer's disease: biological aspects, therapeutic perspectives and diagnostic tools [J]. J Phys Condens Matter, 2012, 24(24): 244102.
3
Hunt DL, Castillo PE. Synaptic plasticity of NMDA receptors: mechanisms and functional implications [J]. Curr Opin Neurobiol, 2012, 22(3): 496-508.
4
Vergara C, Houben S, Suain V, et al. Amyloid-beta pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo [J]. Acta Neuropathol, 2019, 137(3): 397-412.
5
HöLTTä M, Hansson O, Andreasson U, et al. Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease [J]. PloS One, 2013, 8(6): e66381.
6
Wischik CM, Novak M, Edwards PC, et al. Structural characterization of the core of the paired helical filament of Alzheimer disease [J]. Proc Natl Acad Sci U S A, 1988, 85(13): 4884-4888.
7
Kimura T, Whitcomb DJ, Jo J, et al. Microtubule-associated protein tau is essential for long-term depression in the hippocampus [J]. Philos Trans R Soc Lond B Biol Sci, 2014, 369(1633): 20130144.
8
Busche MA, Wegmann S, Dujardin S, et al. Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer models in vivo [J]. Nat Neurosci, 2019, 22(1): 57-64.
9
Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease [J]. Acta Neuropathol, 2017, 133(5): 665-704.
10
Jadhav S, Katina S, Kovac A, et al. Truncated tau deregulates synaptic markers in rat model for human tauopathy [J]. Front Cell Neurosci, 2015, 9: 24.
11
Takeda S, Wegmann S, Cho H, et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain [J]. Nat Commun, 2015, 6: 8490.
12
Shafiei SS, Guerrero-Munoz MJ, Castillo-Carranza DL. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage [J]. Front Aging Neurosci, 2017, 9: 83.
13
Mably AJ, Gereke BJ, Jones DT, et al. Impairments in spatial representations and rhythmic coordination of place cells in the 3xTg mouse model of Alzheimer's disease [J]. Hippocampus, 2017, 27(4): 378-392.
14
Gillespie AK, Jones EA, Lin YH, et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples [J]. Neuron, 2016, 90(4): 740-751.
15
Prusiner SB. A unifying role for prions in neurodegenerative diseases [J]. Science, 2012, 336(6088): 1511-1513.
16
Condello C, Stoehr J. Abeta propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease [J]. Neurobiol Dis, 2018, 109(Pt B): 191-200.
17
Hsu TM, Noble EE, Reiner DJ, et al. Hippocampus ghrelin receptor signaling promotes socially-mediated learned food preference [J]. Neuropharmacology, 2018, 131: 487-496.
18
Tian J, Guo L, Sui S, et al. Disrupted hippocampal growth hormone secretagogue receptor 1alpha interaction with dopamine receptor D1 plays a role in Alzheimer's disease [J]. Sci Transl Med, 2019, 11(505): eaav6278.
19
Jeong YO, Shin SJ, Park JY, et al. MK-0677, a ghrelin agonist, alleviates amyloid beta-related pathology in 5XFAD mice, an animal model of Alzheimer's disease [J]. Int J Mol Sci, 2018, 19(6): 1800.
20
Nortley R, Korte N, Izquierdo P, et al. Amyloid beta oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes [J]. Science, 2019, 365(6450): aav9518.
21
徐玉振, 王茜, 单敏, 等. 高压氧治疗对阿尔茨海默病患者认知功能及血清Humanin水平的影响 [J/OL]. 中华诊断学电子杂志, 2019, 7(2): 83-86.
22
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, et al. Alzheimer's disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection [J]. Neuron, 2018, 99(1): 56-63.e3.
23
Ide M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer's disease [J]. PLoS One, 2016, 11(3): e0151081.
24
Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors [J]. Sci Adv, 2019, 5(1): eaau3333.
25
Zhou R, Yang G, Shi Y. Dominant negative effect of the loss-of-function gamma-secretase mutants on the wild-type enzyme through heterooligomerization [J]. Proc Natl Acad Sci U S A, 2017, 114(48): 12731-12736.
26
Quigley EMM. Microbiota-brain-gut axis and neurodegenerative diseases [J]. Curr Neurol Neurosci Rep, 2017, 17(12): 94.
27
Köhler CA, Maes M, Slyepchenko A, et al. The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: mechanisms and pathophysiological role in Alzheimer's disease [J]. Curr Pharml Des, 2016, 22(40): 6152-6166.
28
Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis [J]. Cell, 2015, 161(2): 264-276.
29
Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels [J]. Nature, 2015, 523(7560): 337-341.
30
Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson's disease [J]. World J Gastroenterol, 2015, 21(37): 10609-10620.
31
Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer's disease [J]. J Neurogastroenterol Motil, 2019, 25(1): 48-60.
32
Wang X, Zhu M, Hjorth E, et al. Resolution of inflammation is altered in Alzheimer's disease [J]. Alzheimer's Dement, 2015, 11(1): 40-50.e2.
33
Zhu M, Wang X, Hjorth E, et al. Pro-resolving lipid mediators improve neuronal survival and increase Aβ 42 phagocytosis [J]. Mol Neurobiol, 2016, 53(4): 2733-2749.
34
Zhu M, Wang X, Sun L, et al. Can inflammation be resolved in Alzheimer's disease? [J]. Ther Adv Neurol Disord, 2018, 11: 1756286418791107.
35
Lee JY, Han SH, Park MH, et al. N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer's disease [J]. Nat Commun, 2020, 11(1): 2358.
36
Brodbeck J, Mcguire J, Liu Z, et al. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors [J]. J Biol Chem, 2011, 286(19): 17217-17226.
37
Castellano JM, Kim J, Stewart FR, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance [J]. Sci Transl Med, 2011, 3(89): 89ra57.
38
Giri M, Zhang M, Lü Y. Genes associated with Alzheimer's disease: an overview and current status [J]. Clin Interv Aging, 2016, 11: 665-681.
39
Hudry E, Dashkoff J, Roe AD, et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain [J]. Sci Transl Med, 2013, 5(212): 212ra161.
40
Pankiewicz JE, Guridi M, Kim J, et al. Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice [J]. Acta Neuropathol Commun, 2014, 2: 75.
[1] 李智, 冯芸. NF-κB 与MAPK 信号通路及其潜在治疗靶点在急性呼吸窘迫综合征中的研究进展[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(05): 840-843.
[2] 刘璐璐, 何羽. 慢性阻塞性肺病患者睡眠障碍的研究进展[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(05): 836-839.
[3] 廖江荣, 吴秀琳, 陈光春, 郭亮, 吕慈, 蔡俊, 陈夕. 急性主动脉夹层并发急性肺损伤的研究新进展[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(03): 488-492.
[4] 陈华萍, 陈晓龙, 胡明冬. 难治性哮喘的发病机制及诊治进展[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(01): 144-147.
[5] 陈惠燕, 吴瑶, 黄宗炫, 卜歆, 王庆惠, 纪辉涛, 陈银珍, 赵虎. 肾间质纤维化中胶原/DDR2 信号活化对肾成纤维细胞增殖和迁移功能影响的实验研究[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(05): 294-302.
[6] 赵静, 张嘉欣, 高言, 谢席胜. 微小病变肾病的发病机制及治疗研究进展[J/OL]. 中华肾病研究电子杂志, 2024, 13(04): 207-212.
[7] 孙鼎, 王滨, 陈香美, 陈意志. 热应激肾病的研究进展[J/OL]. 中华肾病研究电子杂志, 2024, 13(03): 170-176.
[8] 贾红艳, 王丹, 张冉冉, 马茜, 焦永红. 基于全外显子组测序探寻Möbius综合征发病机制的遗传学研究[J/OL]. 中华眼科医学杂志(电子版), 2024, 14(03): 146-154.
[9] 王燕, 梁海乾, 郭姗姗. 炎症小体在创伤性脑损伤中作用的研究进展[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(03): 177-181.
[10] 安亚楠, 王端然, 郭甜甜, 武希润. 幽门螺杆菌阴性胃黏膜相关淋巴组织淋巴瘤的研究进展[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(03): 268-274.
[11] 刘琦, 王守凯, 王帅, 苏雨晴, 马壮, 陈海军, 司丕蕾. 乳腺癌肿瘤内微生物组的研究进展[J/OL]. 中华临床医师杂志(电子版), 2024, 18(09): 841-845.
[12] 陈雪芬, 韦虹羽, 孙起翔, 赵华, 闫萍, 龚臣. 肺肝样腺癌诊治研究进展[J/OL]. 中华临床医师杂志(电子版), 2024, 18(01): 83-86.
[13] 厉若男, 宋进, 王玉忠. 带状疱疹后神经痛的发病机制和诊治研究进展[J/OL]. 中华诊断学电子杂志, 2024, 12(03): 199-205.
[14] 王可涵, 许涛, 周全红. 围术期谵妄与应激的研究进展[J/OL]. 中华老年病研究电子杂志, 2024, 11(03): 45-49.
[15] 陆远欣, 龚莉琳, 曾梦华. 肥胖与非酒精性脂肪肝研究进展[J/OL]. 中华肥胖与代谢病电子杂志, 2024, 10(02): 113-119.
阅读次数
全文


摘要