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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

在阿尔茨海默氏病大脑的海马蠕动后样本中，亨廷顿水平升高

卷 17, 期 9, 2020

页: [858 - 867] 页: 10

弟呕挨: 10.2174/1567205017666201203125622

价格: $65

摘要

背景：我们最近确定了亨廷顿氏病的致病蛋白亨廷顿（Htt），在AD淀粉样前体蛋白（APP）敲入小鼠模型中是阿尔茨海默氏病（AD）病理的介质。这一发现促使我们检查Htt是否在AD患者的大脑中积累，以及AD大脑中是否存在Htt细胞类型。 目的：探讨AD患者海马和额叶皮层Htt的位置和水平是否受到影响。 方法：使用免疫组织化学方法对AD患者（n = 11）和对照组（n = 11）的大脑进行Htt染色，并对Htt的信号强度进行定量并定位在亚区域和神经元中。共聚焦显微镜用于表征神经元Htt定位及其与tau缠结和星形胶质细胞的关系。 结果：齿状回颗粒层，海马CA1和CA3以及额叶皮层III层的神经元细胞中的Htt水平升高。在体细胞，核周间隙，细神经突和锥体神经元核中发现了Htt。 Htt存在于含有tau缠结的神经元中，但不与星形胶质细胞共定位。 结论：Htt聚集在锥体神经元丰富的区域，包括与记忆和额叶皮层III相关的海马亚区。 Htt在AD中的积累显示出明显的细胞和形态学模式，并且在星形胶质细胞中不存在。显然，有必要进行进一步的研究来阐明Htt作为AD病理介质的作用以及在未来的治疗策略中Htt作为靶标的潜在用途。

关键词: 阿尔茨海默氏病，共聚焦显微镜，GFAP，海马，人脑，亨廷顿蛋白，免疫组化，验尸。

« Previous
[1]
Prince MJ. World Alzheimer Report 2015. The Global Impact of Dementia 2015 https://www.alz.co.uk/research/world-report-2015
[2]
Nichols E, Szoeke CEI, Vollset SE, et al. GBD 2016 Dementia Collaborators Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(1): 88-106.
[http://dx.doi.org/10.1016/S1474-4422(18)30403-4 ] [PMID: 30497964]
[3]
Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15(5): 455-532.
[http://dx.doi.org/10.1016/S1474-4422(16)00062-4 ] [PMID: 26987701]
[4]
Wimo A, Guerchet M, Ali G-C, et al. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement 2017; 13(1): 1-7.
[http://dx.doi.org/10.1016/j.jalz.2016.07.150 ] [PMID: 27583652]
[5]
Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs 2017; 26(6): 735-9.
[http://dx.doi.org/10.1080/13543784.2017.1323868 ] [PMID: 28460541]
[6]
Yiannopoulou KG, Papageorgiou SG. Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disorder 2013; 6(1): 19-33.
[http://dx.doi.org/10.1177/1756285612461679 ] [PMID: 23277790]
[7]
Brotchie J, Bezard E, Jenner P. Pathophysiology, pharmacology and biochemistry of dyskinesia. Academic Press 2011.
[8]
Daldin M, Fodale V, Cariulo C, et al. Polyglutamine expansion affects huntingtin conformation in multiple Huntington’s disease models Sci Rep 7(1): 2017; 5070https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505970/
[http://dx.doi.org/10.1038/s41598-017-05336-7]
[9]
Fodale V, Kegulian NC, Verani M, et al. Polyglutamine- and temperature-dependent conformational rigidity in mutant huntingtin revealed by immunoassays and circular dichroism spectroscopy. PLoS One 2014; 9(12)e112262
[http://dx.doi.org/10.1371/journal.pone.0112262 ] [PMID: 25464275]
[10]
Bano D, Zanetti F, Mende Y, Nicotera P. Neurodegenerative processes in Huntington’s disease. Cell Death Dis 2011; 2e228
[http://dx.doi.org/10.1038/cddis.2011.112 ] [PMID: 22071633]
[11]
El-Daher M-T, Hangen E, Bruyère J, et al. Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J 2015; 34(17): 2255-71.
[http://dx.doi.org/10.15252/embj.201490808 ] [PMID: 26165689]
[12]
Aziz NA, van der Burg JMM, Tabrizi SJ, Landwehrmeyer GB. Overlap between age-at-onset and disease-progression determinants in Huntington disease. Neurology 2018; 90(24): e2099-106.
[http://dx.doi.org/10.1212/WNL.0000000000005690 ] [PMID: 29743208]
[13]
Tan Z, Dai W, van Erp TGM, et al. Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin. Mol Psychiatry 2015; 20(11): 1286-93.
[http://dx.doi.org/10.1038/mp.2015.81 ] [PMID: 26100538]
[14]
Niemelä V, Landtblom A-M, Blennow K, Sundblom J. Tau or neurofilament light-Which is the more suitable biomarker for Huntington’s disease? PLoS One 2017; 12(2)e0172762
[http://dx.doi.org/10.1371/journal.pone.0172762 ] [PMID: 28241046]
[15]
Rodrigues FB, Byrne L, McColgan P, et al. Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington’s disease. J Neurochem 2016; 139(1): 22-5.
[http://dx.doi.org/10.1111/jnc.13719 ] [PMID: 27344050]
[16]
Singhrao SK, Thomas P, Wood JD, et al. Huntingtin protein colocalizes with lesions of neurodegenerative diseases: An investigation in Huntington’s, Alzheimer’s, and Pick’s diseases. Exp Neurol 1998; 150(2): 213-22.
[http://dx.doi.org/10.1006/exnr.1998.6778 ] [PMID: 9527890]
[17]
Förstl H, Kurz A. Clinical features of Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 1999; 249(6): 288-90.
[http://dx.doi.org/10.1007/s004060050101 ] [PMID: 10653284]
[18]
Roos RA. Huntington’s disease: A clinical review. Orphanet J Rare Dis 2010; 5: 40.
[http://dx.doi.org/10.1186/1750-1172-5-40 ] [PMID: 21171977]
[19]
De Strooper B, Vassar R, Golde T. The secretases: Enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010; 6(2): 99-107.
[http://dx.doi.org/10.1038/nrneurol.2009.218 ] [PMID: 20139999]
[20]
Reiner A, Dragatsis I, Zeitlin S, Goldowitz D. Wild-type huntingtin plays a role in brain development and neuronal survival. Mol Neurobiol 2003; 28(3): 259-76.
[http://dx.doi.org/10.1385/MN:28:3:259 ] [PMID: 14709789]
[21]
Nicolas M, Hassan BA. Amyloid precursor protein and neural development. Development 2014; 141(13): 2543-8.
[http://dx.doi.org/10.1242/dev.108712 ] [PMID: 24961795]
[22]
Menéndez-González M, Clarimón J, Rosas-Allende I, et al. HTT gene intermediate alleles in neurodegeneration: Evidence for association with Alzheimer’s disease. Neurobiol Aging 2019; 76: 215.e9-215.e14.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.014 ] [PMID: 30583877]
[23]
Hartlage-Rübsamen M, Ratz V, Zeitschel U, et al. Endogenous mouse huntingtin is highly abundant in cranial nerve nuclei, co-aggregates to Abeta plaques and is induced in reactive astrocytes in a transgenic mouse model of Alzheimer’s disease. Acta Neuropathol Commun 2019; 7(1): 79.
[http://dx.doi.org/10.1186/s40478-019-0726-2 ] [PMID: 31109380]
[24]
Wood TE, Barry J, Yang Z, Cepeda C, Levine MS, Gray M. Mutant huntingtin reduction in astrocytes slows disease progression in the BACHD conditional Huntington’s disease mouse model. Hum Mol Genet 2019; 28(3): 487-500.
[PMID: 30312396]
[25]
Bradford J, Shin J-Y, Roberts M, Wang C-E, Li X-J, Li S. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci USA 2009; 106(52): 22480-5.
[http://dx.doi.org/10.1073/pnas.0911503106 ] [PMID: 20018729]
[26]
Garcia VJ, Rushton DJ, Tom CM, et al. Huntington’s disease patient-derived astrocytes display electrophysiological impairments and reduced neuronal support Front Neurosci 2019; 13: 669https://www.frontiersin.org/articles/10.3389/fnins.2019.00669/full
[http://dx.doi.org/10.3389/fnins.2019.00669]
[27]
Morris JC, Heyman A, Mohs RC, et al. The consortium to establish a registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 1989; 39(9): 1159-65.
[http://dx.doi.org/10.1212/WNL.39.9.1159 ] [PMID: 2771064]
[28]
Mann DM. Pyramidal nerve cell loss in Alzheimer’s disease. Neurodegeneration 1996; 5(4): 423-7.
[http://dx.doi.org/10.1006/neur.1996.0057 ] [PMID: 9117557]
[29]
Cowan CM, Raymond LA. Selective neuronal degeneration in Huntington’s disease. Curr Top Dev Biol 2006; 75: 25-71.
[http://dx.doi.org/10.1016/S0070-2153(06)75002-5 ] [PMID: 16984809]
[30]
Bartus RT, Dean RL III, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217(4558): 408-14.
[http://dx.doi.org/10.1126/science.7046051 ] [PMID: 7046051]
[31]
Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM. Alzheimer’s disease: Targeting the cholinergic system. Curr Neuropharmacol 2016; 14(1): 101-15.
[http://dx.doi.org/10.2174/1570159X13666150716165726 ] [PMID: 26813123]
[32]
Dannenberg H, Young K, Hasselmo M. Modulation of hippocampal circuits by muscarinic and nicotinic receptors Front Neural Circuits 2017; 11: 102.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733553/
[http://dx.doi.org/10.3389/fncir.2017.00102 ]
[33]
Arendt T, Brückner MK, Morawski M, Jäger C, Gertz H-J. Early neurone loss in Alzheimer’s disease: Cortical or subcortical? Acta Neuropathol Commun 2015; 3: 10.
[http://dx.doi.org/10.1186/s40478-015-0187-1]
[34]
Estrada-Sánchez AM, Rebec GV. Role of cerebral cortex in the neuropathology of Huntington’s disease Front Neural Circuits 2013; 7: 19.https://www.frontiersin.org/articles/10.3389/fncir.2013.00019/full
[http://dx.doi.org/10.3389/fncir.2013.00019]
[35]
Palpagama TH, Waldvogel HJ, Faull RLM, Kwakowsky A. The role of microglia and astrocytes in Huntington’s disease Front Mol Neurosci 2019; 12: 258.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824292/
[http://dx.doi.org/10.3389/fnmol.2019.00258]
[36]
Gray M. Astrocytes in Huntington’s Disease. Adv Exp Med Biol 2019; 1175: 355-81.
[http://dx.doi.org/10.1007/978-981-13-9913-8_14 ] [PMID: 31583595]
[37]
Chun H, Lee CJ. Reactive astrocytes in Alzheimer’s disease: A double-edged sword. Neurosci Res 2018; 126: 44-52.
[http://dx.doi.org/10.1016/j.neures.2017.11.012 ] [PMID: 29225140]
[38]
Ehrnhoefer DE, Butland SL, Pouladi MA, Hayden MR. Mouse models of Huntington disease: Variations on a theme. Dis Model Mech 2009; 2(3-4): 123-9.
[http://dx.doi.org/10.1242/dmm.002451 ] [PMID: 19259385]
[39]
Aronin N, Chase K, Young C, et al. CAG expansion affects the expression of mutant Huntingtin in the Huntington’s disease brain. Neuron 1995; 15(5): 1193-201.
[http://dx.doi.org/10.1016/0896-6273(95)90106-X ] [PMID: 7576661]
[40]
Boutell JM, Thomas P, Neal JW, et al. Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 1999; 8(9): 1647-55.
[http://dx.doi.org/10.1093/hmg/8.9.1647 ] [PMID: 10441327]
[41]
Xia J, Lee DH, Taylor J, Vandelft M, Truant R. Huntingtin contains a highly conserved nuclear export signal. Hum Mol Genet 2003; 12(12): 1393-403.
[http://dx.doi.org/10.1093/hmg/ddg156 ] [PMID: 12783847]
[42]
Scherzinger E, Sittler A, Schweiger K, et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology. Proc Natl Acad Sci USA 1999; 96(8): 4604-9.
[http://dx.doi.org/10.1073/pnas.96.8.4604 ] [PMID: 10200309]
[43]
Schedin-Weiss S, Nilsson P, Sandebring-Matton A, et al. Proteomics time-course study of App knock-in mice reveals novel presymptomatic Aβ42-induced pathways to Alzheimer’s disease pathology. J Alzheimers Dis 2020; 75(1): 321-35.
[http://dx.doi.org/10.3233/JAD-200028 ] [PMID: 32280097]
[44]
Debatin L, Streffer J, Geissen M, Matschke J, Aguzzi A, Glatzel M. Association between deposition of beta-amyloid and pathological prion protein in sporadic Creutzfeldt-Jakob disease. Neurodegener Dis 2008; 5(6): 347-54.
[http://dx.doi.org/10.1159/000121389 ] [PMID: 18349519]
[45]
Hamilton RL. Lewy bodies in Alzheimer’s disease: A neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 2000; 10(3): 378-84.
[http://dx.doi.org/10.1111/j.1750-3639.2000.tb00269.x ] [PMID: 10885656]
[46]
Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H. Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol 1998; 96(2): 116-22.
[http://dx.doi.org/10.1007/s004010050870 ] [PMID: 9705125]
[47]
Borrell-Pagès M, Zala D, Humbert S, Saudou F. Huntington’s disease: From huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci 2006; 63(22): 2642-60.
[http://dx.doi.org/10.1007/s00018-006-6242-0 ] [PMID: 17041811]
[48]
Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington’s Disease pathology. Curr Trends Neurol 2011; 5: 65-78.
[PMID: 22180703]
[49]
Atwal RS, Xia J, Pinchev D, Taylor J, Epand RM, Truant R. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet 2007; 16(21): 2600-15.
[http://dx.doi.org/10.1093/hmg/ddm217 ] [PMID: 17704510]
[50]
A study to evaluate the efficacy and safety of intrathecally administered RO7234292 (RG6042) in patients with manifest Huntington’s disease. Available from: https://clinicaltrials.gov/ct2/show/study/NCT03761849
[51]
Safety and proof-of-concept (POC) study with amt-130 in adults with early manifest Huntington disease. https://clinicaltrials.gov/ct2/show/NCT04120493

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