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文献精选 > 高引权威"阿尔茨海默病"文献

Alzheimer's disease. ​

文献信息 ​

PMID21576255
期刊Cold Spring Harbor perspectives in biology
影响因子8.4
JCR 分区Q1
发表年份2011
被引次数214
关键词阿尔茨海默病, 神经退行性疾病, 蛋白质错误折叠, 淀粉样蛋白, tau蛋白
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1943-0264
期号3(7)
作者Dennis J Selkoe

一句话小结 ​

本研究回顾了神经退行性疾病，特别是阿尔茨海默病的分子机制，强调了正常神经元蛋白质的错误折叠与聚集对细胞造成的毒性影响。通过揭示淀粉样β蛋白和tau蛋白的变化，研究为临床治疗提供了新的机制靶点，并推动了相关临床试验的开展。

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阿尔茨海默病 · 神经退行性疾病 · 蛋白质错误折叠 · 淀粉样蛋白 · tau蛋白

摘要 ​

在过去三十年中，生化病理学和人类遗传学的进展揭示了生物医学中最神秘的主题之一——神经退行性疾病。阿尔茨海默病、帕金森病和亨廷顿病等神经系统的名字命名疾病，长期以来因缺乏机制理解而被忽视，但我们对其分子基础的理解已取得显著进展。这些疾病及相关疾病的一个核心主题是某些正常可溶性神经元蛋白质可以错误折叠并聚集成寡聚物和淀粉样纤维，这些结构可能导致深远的细胞毒性。也许最重要的例子，既体现在其社会影响上，也体现在知识向临床转化的进展上，就是阿尔茨海默病（AD）。在这里，我们将回顾该疾病的经典蛋白损伤，这些损伤为病因和发病机制提供了路线图。我们还将讨论阐明家族性阿尔茨海默病的基因型与表型关系的重要性，强调了两种本应可溶的蛋白质——淀粉样β蛋白和tau蛋白的错误折叠和改变的蛋白稳态，这暗示了基于机制的治疗靶点，这些靶点已导致临床试验的开展。

英文摘要 ​

Over the last three decades, advances in biochemical pathology and human genetics have illuminated one of the most enigmatic subjects in biomedicine--neurodegeneration. Eponymic diseases of the nervous system such as Alzheimer's, Parkinson's, and Huntington's diseases that were long characterized by mechanistic ignorance have yielded striking progress in our understanding of their molecular underpinnings. A central theme in these and related disorders is the concept that certain normally soluble neuronal proteins can misfold and aggregate into oligomers and amyloid fibrils which can confer profound cytotoxicity. Perhaps the foremost example, both in terms of its societal impact and how far knowledge has moved toward the clinic, is that of Alzheimer's disease (AD). Here, we will review the classical protein lesions of the disorder that have provided a road map to etiology and pathogenesis. We will discuss how elucidating the genotype-to-phenotype relationships of familial forms of Alzheimer's disease has highlighted the importance of the misfolding and altered proteostasis of two otherwise soluble proteins, amyloid β-protein and tau, suggesting mechanism-based therapeutic targets that have led to clinical trials.

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主要研究问题 ​

  1. 阿尔茨海默病的早期生物标志物有哪些，如何在临床中应用？
  2. 生活方式干预在阿尔茨海默病预防中的具体作用是什么？
  3. 在阿尔茨海默病的诊断中，tau PET与传统成像技术相比有哪些优势？
  4. 目前针对阿尔茨海默病的临床试验主要集中在哪些治疗方法上？
  5. 认知健康个体中主观认知下降的患者如何被用于阿尔茨海默病的早期筛查？

核心洞察 ​

研究背景和目的 ​

在过去的三十年中，生化病理学和人类遗传学的进展使神经退行性疾病这一复杂领域得到了显著的发展。阿尔茨海默病（AD）、帕金森病和亨廷顿病等神经系统的特征性疾病在机制上的无知已逐渐被对其分子基础的深入理解所取代。本研究旨在回顾阿尔茨海默病的经典蛋白质损伤，并探讨其病因和发病机制，为相关疾病的治疗提供理论基础。

主要方法/材料/实验设计 ​

本研究采用文献综述的方式，重点分析了阿尔茨海默病的基因型与表型之间的关系，以及相关蛋白质（如淀粉样β蛋白和tau蛋白）的错误折叠和蛋白质稳态改变对疾病发展的影响。

以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  • 阿尔茨海默病的主要病理特征包括淀粉样斑块和神经纤维缠结，这些都是由淀粉样β蛋白和tau蛋白的聚集所导致。
  • 通过对家族性阿尔茨海默病的基因研究，发现了与疾病相关的突变，这些突变增强了蛋白质的错误折叠倾向。
  • 研究强调了错误折叠蛋白质对细胞的细胞毒性影响，提示其在疾病发病机制中的核心作用。

主要结论/意义/创新性 ​

本研究的主要结论是，淀粉样β蛋白和tau蛋白的错误折叠及其聚集是阿尔茨海默病发病的关键机制。通过深入理解这些机制，研究者能够识别新的机制基础的治疗靶点，从而推动临床试验的开展。这为阿尔茨海默病的治疗提供了新的方向，可能会带来突破性的进展。

研究局限性和未来方向 ​

  • 研究的局限性在于主要依赖文献回顾，缺乏实验数据支持，可能导致某些结论的局限性。
  • 未来的研究方向应集中在以下几个方面：
    • 进一步探索其他神经退行性疾病中类似的蛋白质错误折叠机制。
    • 开展更多临床试验，以验证新识别的治疗靶点的有效性。
    • 加强对蛋白质稳态调控机制的研究，为开发新型治疗策略提供理论依据。

参考文献 ​

  1. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. - L Mucke;E Masliah;G Q Yu;M Mallory;E M Rockenstein;G Tatsuno;K Hu;D Kholodenko;K Johnson-Wood;L McConlogue - The Journal of neuroscience : the official journal of the Society for Neuroscience (2000)
  2. Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. - J Larson;G Lynch;D Games;P Seubert - Brain research (1999)
  3. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. - M Hong;V Zhukareva;V Vogelsberg-Ragaglia;Z Wszolek;L Reed;B I Miller;D H Geschwind;T D Bird;D McKeel;A Goate;J C Morris;K C Wilhelmsen;G D Schellenberg;J Q Trojanowski;V M Lee - Science (New York, N.Y.) (1998)
  4. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. - S Gilman;M Koller;R S Black;L Jenkins;S G Griffith;N C Fox;L Eisner;L Kirby;M Boada Rovira;F Forette;J-M Orgogozo; - Neurology (2005)
  5. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. - C A Lemere;J K Blusztajn;H Yamaguchi;T Wisniewski;T C Saido;D J Selkoe - Neurobiology of disease (1996)
  6. Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). - H H Slunt;G Thinakaran;C Von Koch;A C Lo;R E Tanzi;S S Sisodia - The Journal of biological chemistry (1994)
  7. Microglial cells and amyloid beta protein (A beta) deposition; association with A beta 40-containing plaques. - D M Mann;T Iwatsubo;H Fukumoto;Y Ihara;A Odaka;N Suzuki - Acta neuropathologica (1995)
  8. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. - W Xia;J Zhang;R Perez;E H Koo;D J Selkoe - Proceedings of the National Academy of Sciences of the United States of America (1997)
  9. Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. - M C Irizarry;F Soriano;M McNamara;K J Page;D Schenk;D Games;B T Hyman - The Journal of neuroscience : the official journal of the Society for Neuroscience (1997)
  10. Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. - K C Evans;E P Berger;C G Cho;K H Weisgraber;P T Lansbury - Proceedings of the National Academy of Sciences of the United States of America (1995)

引用本文的文献 ​

  1. Neurodegeneration the RNA way. - Abigail J Renoux;Peter K Todd - Progress in neurobiology (2012)
  2. Genetics of dementia. - Henry L Paulson;Indu Igo - Seminars in neurology (2011)
  3. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. - Yichen Shi;Peter Kirwan;James Smith;Glenn MacLean;Stuart H Orkin;Frederick J Livesey - Science translational medicine (2012)
  4. Inverse susceptibility to oxidative death of lymphocytes obtained from Alzheimer's patients and skin cancer survivors: increased apoptosis in Alzheimer's and reduced necrosis in cancer. - Maria I Behrens;Monica Silva;Felipe Salech;Daniela P Ponce;Daniela Merino;Mariana Sinning;Chengjie Xiong;Catherine M Roe;Andrew F G Quest - The journals of gerontology. Series A, Biological sciences and medical sciences (2012)
  5. Could immunomodulation be used to prevent prion diseases? - Thomas Wisniewski;Fernando Goñi - Expert review of anti-infective therapy (2012)
  6. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. - Christopher J Guerriero;Jeffrey L Brodsky - Physiological reviews (2012)
  7. Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration. - Sebastián Bernales;Marisol Morales Soto;Emma McCullagh - Frontiers in aging neuroscience (2012)
  8. Gender, sex steroid hormones, and Alzheimer's disease. - Rebekah S Vest;Christian J Pike - Hormones and behavior (2013)
  9. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. - Maria L Maccecchini;Mee Young Chang;Catherine Pan;Varghese John;Henrik Zetterberg;Nigel H Greig - Journal of neurology, neurosurgery, and psychiatry (2012)
  10. Alzheimer's disease in a dish: promises and challenges of human stem cell models. - Jessica E Young;Lawrence S B Goldstein - Human molecular genetics (2012)

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