Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.
Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.
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DOI：
10.1007/s00401-015-1386-3
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发表时间：
2015-02
影响因子：
12.7
通讯作者：
Klein WL
中科院分区：
文献类型：
--
作者：
Viola KL;Klein WL
蛋白质聚集是许多疾病的常见现象，包括朊病毒、糖尿病、帕金森病和阿尔茨海默病。在过去的 15 年里，人们对这些蛋白质病的结构基础的理解发生了范式转变。这种转变的先例来自于对可溶性 Aβ 寡聚体 (AβO) 的研究，这种毒素现在被广泛认为会引发神经元损伤，导致阿尔茨海默氏痴呆。有毒的 AβO 在 AD 大脑中积聚，并构成沉积在淀粉样斑块中的疾病定义 Aβ 原纤维的长寿命替代品。使用无原纤维 AβO 溶液的关键实验表明，虽然 Aβ 对于记忆丧失至关重要，但淀粉样蛋白沉积物中的原纤维 Aβ 并不是作用因素。 AβO 诱导的类似 AD 的细胞病理表明，它们的影响为 AD 发病机制提供了统一的机制，解释了为什么早期疾病对记忆具有特异性，并解释了 AD 神经病理学的主要方面。正在积极研究触发机制的替代想法。一些研究支持将 AβO 插入膜中，而其他证据则支持特定突触处的配体样积累。已经提出了十多种候选毒素受体。 AβO 结合触发关键突触蛋白的重新分布，并诱导代谢型和离子型谷氨酸受体过度活跃。这会导致 Ca2+ 超载并引发 AD 神经病理学的主要方面，包括 tau 蛋白过度磷酸化、胰岛素抵抗、氧化应激和突触损失。由于已鉴定出不同种类的 AβO，因此剩下的问题是哪种寡聚物是主要的致病元凶。有人提出可能有不止一个物种发挥作用。尽管存在一些关键的未知因素，AβO 的临床相关性已经确定，并且新的研究开始指出糖尿病和高胆固醇血症等合并症是病因因素。由于致病性 AβO 出现在疾病早期，因此它们为治疗和诊断提供了有吸引力的靶点。有前景的治疗策略包括使用 CNS 胰岛素信号增强剂来防止毒素的存在，并通过使用高度特异性的 AβO 抗体消除毒素。 AβO 在 CSF 中的 AD 依赖性积累表明它们作为生物标志物的潜在用途，而新的 AβO 探针为脑成像打开了大门。总体而言，目前的证据表明，Aβ寡聚物为阿尔茨海默病的病因、治疗和诊断提供了实质性的分子基础。
Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer’s disease.
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影响因子：
--
作者：
Craft, Suzanne;Baker, Laura D.;Montine, Thomas J.;Minoshima, Satoshi;Watson, G. Stennis;Claxton, Amy;Arbuckle, Matthew;Callaghan, Maureen;Tsai, Elaine;Plymate, Stephen R.;Green, Pattie S.;Leverenz, James;Cross, Donna;Gerton, Brooke
通讯作者：
Gerton, Brooke
影响因子：
3.5
作者：
Boutajangout A;Wisniewski T
通讯作者：
Wisniewski T
影响因子：
6.1
作者：
Domert, Jakob;Rao, Sahana Bhima;Nath, Sangeeta
通讯作者：
Nath, Sangeeta
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
5.6
作者：
de la Monte, Suzanne M.
通讯作者：
de la Monte, Suzanne M.