神经元转化生长因子-β信号通路缺陷会促进神经退行性变和阿尔茨海默病病理改变。
Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology.
作者信息
Tesseur Ina, Zou Kun, Esposito Luke, Bard Frederique, Berber Elisabeth, Can Judith Van, Lin Amy H, Crews Leslie, Tremblay Patrick, Mathews Paul, Mucke Lennart, Masliah Eliezer, Wyss-Coray Tony
机构信息
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
出版信息
J Clin Invest. 2006 Nov;116(11):3060-9. doi: 10.1172/JCI27341.
Abstract
Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the beta-amyloid peptide (Abeta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (TbetaRII) is mainly expressed by neurons, and that TbetaRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted Abeta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted Abeta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD.
摘要
阿尔茨海默病（AD）的特征是进行性神经退行性变以及β-淀粉样肽（Aβ）在大脑中的积累，但尚不清楚是什么使神经元易发生变性。我们报告，转化生长因子-βⅡ型受体（TβRII）主要由神经元表达，并且在人类AD大脑中TβRII水平降低，且与该疾病的病理特征相关。在小鼠中降低神经元转化生长因子-β信号传导导致年龄依赖性神经退行性变，并在AD小鼠模型中促进Aβ积累和树突丢失。在培养细胞中，降低的转化生长因子-β信号传导导致神经元变性，并导致分泌的Aβ和β-分泌酶切割的可溶性淀粉样前体蛋白水平升高。这些结果表明，降低的神经元转化生长因子-β信号传导会增加体内年龄依赖性神经退行性变和AD样疾病。因此，增加神经元转化生长因子-β信号传导可能会减少神经退行性变，并对AD有益。
相似文献
1
Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology.神经元转化生长因子-β信号通路缺陷会促进神经退行性变和阿尔茨海默病病理改变。
J Clin Invest. 2006 Nov;116(11):3060-9. doi: 10.1172/JCI27341.
2
Dysfunction of TGF-beta signaling in Alzheimer's disease.阿尔茨海默病中转化生长因子-β信号传导功能障碍。
J Clin Invest. 2006 Nov;116(11):2855-7. doi: 10.1172/JCI30284.
3
GPR84 deficiency reduces microgliosis, but accelerates dendritic degeneration and cognitive decline in a mouse model of Alzheimer's disease.GPR84 缺乏可减少小胶质细胞增生，但会加速阿尔茨海默病小鼠模型中的树突退化和认知能力下降。
Brain Behav Immun. 2015 May;46:112-20. doi: 10.1016/j.bbi.2015.01.010. Epub 2015 Jan 28.
4
Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice.补体C3缺乏会导致淀粉样前体蛋白转基因小鼠中β淀粉样蛋白斑块沉积加速、神经退行性变以及小胶质细胞/巨噬细胞表型的改变。
J Neurosci. 2008 Jun 18;28(25):6333-41. doi: 10.1523/JNEUROSCI.0829-08.2008.
5
Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance.阻断成年神经元中的胰岛素样生长因子信号通路可通过清除β-淀粉样蛋白来减轻阿尔茨海默病的病理症状。
J Neurosci. 2015 Aug 19;35(33):11500-13. doi: 10.1523/JNEUROSCI.0343-15.2015.
6
Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.在一种新型阿尔茨海默病转基因模型中，CA1/2区出现大量神经元丢失，伴有神经元内和N端截短的β淀粉样蛋白4 (Abeta42) 积聚。
Am J Pathol. 2004 Oct;165(4):1289-300. doi: 10.1016/s0002-9440(10)63388-3.
7
Transforming growth factor-beta signaling pathway as a therapeutic target in neurodegeneration.转化生长因子-β信号通路作为神经退行性变的治疗靶点
J Mol Neurosci. 2004;24(1):149-53. doi: 10.1385/JMN:24:1:149.
8
APP transgenic modeling of Alzheimer's disease: mechanisms of neurodegeneration and aberrant neurogenesis.阿尔茨海默病的 APP 转基因建模：神经退行性变和异常神经发生的机制。
Brain Struct Funct. 2010 Mar;214(2-3):111-26. doi: 10.1007/s00429-009-0232-6. Epub 2009 Nov 29.
9
Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease.在阿尔茨海默病的转基因小鼠模型中，淀粉样病理与进行性单胺能神经变性有关。
J Neurosci. 2008 Dec 17;28(51):13805-14. doi: 10.1523/JNEUROSCI.4218-08.2008.
10
Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes.唐氏综合征小鼠模型中 Dyrk1A 基因剂量的正常化可挽救几种阿尔茨海默病表型。
Neurobiol Dis. 2017 Oct;106:76-88. doi: 10.1016/j.nbd.2017.06.010. Epub 2017 Jun 21.
引用本文的文献
1
When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer's Neuropathogenesis.当两个世界碰撞：遗传学（APOEε4）与神经炎症（IL-1β）在阿尔茨海默病神经发病机制中的作用及关联
Cells. 2025 Aug 7;14(15):1216. doi: 10.3390/cells14151216.
2
Linking expression and function of Drosophila type-I TGF-β receptor baboon isoforms: Multiple roles of BaboA isoform in shaping of the adult central nervous system.果蝇I型转化生长因子-β受体狒狒亚型的表达与功能关联：BaboA亚型在成年中枢神经系统形成中的多重作用
PLoS One. 2025 May 30;20(5):e0318406. doi: 10.1371/journal.pone.0318406. eCollection 2025.
3
The roles of microglia and astrocytes in neuroinflammation of Alzheimer's disease.小胶质细胞和星形胶质细胞在阿尔茨海默病神经炎症中的作用。
Front Neurosci. 2025 May 7;19:1575453. doi: 10.3389/fnins.2025.1575453. eCollection 2025.
4
Whole Transcriptome RNA-Seq Reveals Drivers of Pathological Dysfunction in a Transgenic Model of Alzheimer's Disease.全转录组RNA测序揭示阿尔茨海默病转基因模型中病理功能障碍的驱动因素。
Mol Neurobiol. 2025 Apr 5. doi: 10.1007/s12035-025-04878-6.
5
Overexpression of TGFBR3 Aggravates Cognitive Impairment and Neuroinflammation by Promoting Microglia M1 Polarization in the APP/PS1 Mouse Model of Alzheimer's Disease.在阿尔茨海默病APP/PS1小鼠模型中，TGFBR3的过表达通过促进小胶质细胞M1极化加重认知障碍和神经炎症。
Mol Neurobiol. 2025 Jun;62(6):7706-7722. doi: 10.1007/s12035-025-04731-w. Epub 2025 Feb 10.
6
Study on the Therapeutic Effects of Bisdemethoxycurcumin on a Cerebral Amyloid Angiopathy Mouse Model Established via Chronic Treatment With Five Vascular Risk Factors.双去甲氧基姜黄素对通过五种血管危险因素长期治疗建立的脑淀粉样血管病小鼠模型的治疗作用研究。
Brain Behav. 2025 Jan;15(1):e70245. doi: 10.1002/brb3.70245.
7
The role of zinc in the premature brain: functions, outcomes and future research perspectives.锌在早产儿大脑中的作用：功能、结局及未来研究展望
Front Pediatr. 2024 Dec 23;12:1496846. doi: 10.3389/fped.2024.1496846. eCollection 2024.
8
The dichotomic role of cytokines in aging.细胞因子在衰老过程中的双重作用。
Biogerontology. 2024 Dec 2;26(1):17. doi: 10.1007/s10522-024-10152-4.
9
The intricate interplay between microglia and adult neurogenesis in Alzheimer's disease.阿尔茨海默病中，小胶质细胞与成体神经发生之间复杂的相互作用。
Front Cell Neurosci. 2024 Sep 18;18:1456253. doi: 10.3389/fncel.2024.1456253. eCollection 2024.
10
Mediterranean Diet Modulation of Neuroinflammation-Related Genes in Elderly Adults at High Cardiovascular Risk.地中海饮食对高心血管风险老年人群神经炎症相关基因的调节作用。
Nutrients. 2024 Sep 18;16(18):3147. doi: 10.3390/nu16183147.
本文引用的文献
1
Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.阿尔茨海默病遗传关联研究的系统荟萃分析：AlzGene数据库
Nat Genet. 2007 Jan;39(1):17-23. doi: 10.1038/ng1934.
2
Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.唐氏综合征小鼠模型中App表达增加会破坏神经生长因子（NGF）的运输并导致胆碱能神经元变性。
Neuron. 2006 Jul 6;51(1):29-42. doi: 10.1016/j.neuron.2006.05.022.
3
In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model.在三体小鼠模型中，体内恢复截短型TrkB.T1受体的生理水平可挽救神经元细胞死亡。
Neuron. 2006 Jul 6;51(1):21-8. doi: 10.1016/j.neuron.2006.06.009.
4
Neurotrophins and dementia--keeping in touch.神经营养因子与痴呆——保持联系
Neuron. 2006 Jul 6;51(1):1-3. doi: 10.1016/j.neuron.2006.06.019.
5
Mapping scores onto stages: mini-mental state examination and clinical dementia rating.将评分映射到分期：简易精神状态检查表和临床痴呆评定量表
Am J Geriatr Psychiatry. 2006 Feb;14(2):139-44. doi: 10.1097/01.JGP.0000192478.82189.a8.
6
Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease.在阿尔茨海默病转基因小鼠模型中，Fyn激酶会导致突触和认知功能障碍。
J Neurosci. 2005 Oct 19;25(42):9694-703. doi: 10.1523/JNEUROSCI.2980-05.2005.
7
Specificity and versatility in tgf-beta signaling through Smads.通过Smads蛋白实现的TGF-β信号传导的特异性和多功能性
Annu Rev Cell Dev Biol. 2005;21:659-93. doi: 10.1146/annurev.cellbio.21.022404.142018.
8
Inducible neuronal expression of transgenic TGF-beta1 in vivo: dissection of short-term and long-term effects.体内转基因TGF-β1的诱导性神经元表达：短期和长期效应剖析
Eur J Neurosci. 2005 Jul;22(1):50-64. doi: 10.1111/j.1460-9568.2005.04189.x.
9
Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells.细胞内产生的β-淀粉样肽可抵消其前体蛋白的抗凋亡功能，并启动促凋亡途径，以便在神经母细胞瘤细胞中被其他损伤激活。
J Neurochem. 2004 Dec;91(6):1260-74. doi: 10.1111/j.1471-4159.2004.02816.x.
10
Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease.早期阿尔茨海默病中皮质TrkA蛋白减少但p75（NTR）蛋白未减少。
Ann Neurol. 2004 Oct;56(4):520-31. doi: 10.1002/ana.20233.
Zotero 插件