Selective Detection of Misfolded Tau From Postmortem Alzheimer's Disease Brains.
Selective Detection of Misfolded Tau From Postmortem Alzheimer's Disease Brains.
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DOI：
10.3389/fnagi.2022.945875
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Tau聚集体存在于称为“Tau病”的多种神经退行性疾病中，包括阿尔茨海默病、皮克病、进行性核上性麻痹和皮质基底节变性。因此，这种错误折叠的tau聚集体是选择性检测和生物标志物发现的潜在来源。在脑组织中存在六种人tau亚型，并且在神经元包涵体中观察到3R和4 R亚型。为了开发AD和相关罕见tau蛋白病的选择性标志物，我们首先使用工程化tau蛋白片段4 RCF作为超灵敏实时振荡诱导转换分析（RT-QuIC）的底物。我们表明，来自患病AD和其他tau蛋白病脑的错误折叠的tau蛋白能够接种重组4 RCF底物。我们进一步扩展到使用六种单独的重组tau同种型作为底物来扩增来自AD脑的错误折叠的tau种子。据我们所知，我们第一次证明，来自死后AD脑组织的错误折叠的tau能够特异性地接种所有六种全长人类tau亚型。我们的结果表明，RT-QuIC分析可以区分AD和其他tau蛋白病与非AD正常对照。我们进一步发现，在不接种和接种AD脑匀浆的条件下，3R-tau同种型显示出比它们的4 R-tau对应物显著更快的聚集动力学。总之，我们的工作提供了错误折叠的tau检测作为诊断AD和相关tau蛋白病的潜在生物标志物的潜在新途径，并提供了对亚型特异性人tau聚集的新见解。
Tau aggregates are present in multiple neurodegenerative diseases known as “tauopathies,” including Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions. To develop selective markers for AD and related rare tauopathies, we first used an engineered tau protein fragment 4RCF as the substrate for ultrasensitive real-time quaking-induced conversion analyses (RT-QuIC). We showed that misfolded tau from diseased AD and other tauopathy brains were able to seed recombinant 4RCF substrate. We further expanded to use six individual recombinant tau isoforms as substrates to amplify misfolded tau seeds from AD brains. We demonstrated, for the first time to our knowledge, that misfolded tau from the postmortem AD brain tissues was able to specifically seed all six full-length human tau isoforms. Our results demonstrated that RT-QuIC analysis can discriminate AD and other tauopathies from non-AD normal controls. We further uncovered that 3R-tau isoforms displayed significantly faster aggregation kinetics than their 4R-tau counterparts under conditions of both no seeding and seeding with AD brain homogenates. In summary, our work offers potential new avenues of misfolded tau detection as potential biomarkers for diagnosis of AD and related tauopathies and provides new insights into isoform-specific human tau aggregation.
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来自阿尔茨海默氏症大脑的独特病理tau构象体传播了非转基因小鼠的tau病理。
DOI：
10.1084/jem.20160833
发表时间：
2016-11-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guo JL;Narasimhan S;Changolkar L;He Z;Stieber A;Zhang B;Gathagan RJ;Iba M;McBride JD;Trojanowski JQ;Lee VM
通讯作者：
Lee VM
影响因子：
7.1
作者：
Dujardin S;Bégard S;Caillierez R;Lachaud C;Carrier S;Lieger S;Gonzalez JA;Deramecourt V;Déglon N;Maurage CA;Frosch MP;Hyman BT;Colin M;Buée L
通讯作者：
Buée L
DOI：
10.1016/j.jalz.2014.02.004
发表时间：
2015-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Blennow K;Dubois B;Fagan AM;Lewczuk P;de Leon MJ;Hampel H
通讯作者：
Hampel H
影响因子：
29
作者：
Gibbons GS;Lee VMY;Trojanowski JQ
通讯作者：
Trojanowski JQ
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA