Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer's disease and track disease progression and cognitive decline.
Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer's disease and track disease progression and cognitive decline.
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DOI：
10.1007/s00401-016-1632-3
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发表时间：
2016-12
影响因子：
12.7
通讯作者：
Platt B
中科院分区：
文献类型：
--
作者：
Koss DJ;Jones G;Cranston A;Gardner H;Kanaan NM;Platt B
人类阿尔茨海默病（AD）的尸检研究在很大程度上未能提供明确的证据来支持最初的淀粉样蛋白级联假说，该假说假定β-淀粉样蛋白（A β）聚集体的沉积是痴呆状态的原因以及诱导tau神经元缠结（NFT）。然而，证据表明，A β斑块和NFT（尽管程度较低）存在于非痴呆个体的大量亚组中。因此，一系列可溶性tau和A β物质最近被认为是疾病相关的毒性实体。尽管将可溶性蛋白纳入修订的淀粉样蛋白级联假说中，但在人类AD发作、进展和认知能力下降的背景下，这些物种的详细表征一直缺乏。在这里，通过tau和A β蛋白质印迹和天然状态斑点印迹方案分析了46例人类病例的外侧颞叶样本（Brodmann 21区）。磷酸化tau（抗体：CP13、AT8和PHF-1）、病理性tau构象（MC-1）和寡聚tau（TOC1）的升高与医学诊断一致（非AD，参见AD）和Braak分期（低、中和高），以及可溶性A β物质（MOAB-2和pyro-glu A β）升高和淀粉样前体蛋白水平下降。观察到个体Braak分期与所有tau标志物以及总可溶性A β的多种认知测量之间存在强相关性。与之前的报告相反，SDS稳定的A β寡聚体（* 56）对于所有分类均不可靠，似乎可能是一种技术假象。重要的是，总可溶性A β的稳健预测值取决于天然状态定量。可溶性组分中tau和A β的升高（Braak阶段2 - 3，参见0)明显早于先前在纤维聚焦疾病进展量表中建立的。总之，这些数据提供了强有力的证据，表明可溶性形式的tau和A β在AD早期共定位，并与疾病进展和认知能力下降密切相关。本文的在线版本（doi：10.1007/s00401 - 016 - 1632 - 3）包含补充材料，可供授权用户使用。
Post-mortem investigations of human Alzheimer’s disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entities. Despite the incorporation of soluble proteins into a revised amyloid cascade hypothesis, a detailed characterization of these species in the context of human AD onset, progression and cognitive decline has been lacking. Here, lateral temporal lobe samples (Brodmann area 21) of 46 human cases were profiled via tau and Aβ Western blot and native state dot blot protocols. Elevations in phospho-tau (antibodies: CP13, AT8 and PHF-1), pathological tau conformations (MC-1) and oligomeric tau (TOC1) agreed with medical diagnosis (non-AD cf. AD) and Braak stage classification (low, intermediate and high), alongside elevations in soluble Aβ species (MOAB-2 and pyro-glu Aβ) and a decline in levels of the amyloid precursor protein. Strong correlations were observed between individual Braak stages and multiple cognitive measures with all tau markers as well as total soluble Aβ. In contrast to previous reports, SDS-stable Aβ oligomers (*56) were not found to be reliable for all classifications and appeared likely to be a technical artefact. Critically, the robust predictive value of total soluble Aβ was dependent on native state quantification. Elevations in tau and Aβ within soluble fractions (Braak stage 2–3 cf. 0) were evident earlier than previously established in fibril-focused disease progression scales. Together, these data provide strong evidence that soluble forms of tau and Aβ co-localise early in AD and are closely linked to disease progression and cognitive decline. The online version of this article (doi:10.1007/s00401-016-1632-3) contains supplementary material, which is available to authorized users.
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DOI：
10.1097/nen.0b013e31802c3e7d
发表时间：
2007-01-01
影响因子：
3.2
作者：
Ferrer, Isidre;Santpere, Gabriel;Kretzschmar, Hans
通讯作者：
Kretzschmar, Hans
影响因子：
2.5
作者：
GOEDERT, M;JAKES, R;VANMECHELEN, E
通讯作者：
VANMECHELEN, E
影响因子：
--
作者：
Fukumoto, H;Cheung, BS;Irizarry, MC
通讯作者：
Irizarry, MC
影响因子：
5.5
作者：
Bitan, G;Fradinger, EA;Teplow, DB
通讯作者：
Teplow, DB
影响因子：
14.5
作者：
Baker-Nigh, Alaina;Vahedi, Shahrooz;Geula, Changiz
通讯作者：
Geula, Changiz