Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain.
Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain.
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DOI：
10.3389/fnins.2018.00267
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发表时间：
2018
影响因子：
4.3
通讯作者：
Hyman BT
中科院分区：
文献类型：
--
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
阿尔茨海默病(AD)的定义是由过度磷酸化的tau聚集体和细胞外淀粉样β-β斑块组成的神经元内神经原纤维缠结(NFT)。Tau病理的存在和通过大脑的扩散按Braak分期进行分类，并被认为与AD的进展相关。几项体外和体内研究已经检验了tau病理从一个神经元转移到下一个神经元的能力，表明tau聚集体的“普里恩”扩散可能是AD Braak tau分期的潜在原因。使用HEK293 TauRD-P301S-CFP/YFP表达生物传感器细胞作为一种高度敏感和特异的工具来鉴定脑裂解物中是否存在种子活性聚集tau-即能够招募和错误折叠单体tau的tau聚集体，我们从只有非常罕见的NFTs的人类病例的内嗅皮层中检测到大量tau种子水平，这表明在明显的tau病理发展之前就存在可溶的tau聚集体。接下来，我们沿着Braak Tau通路的六个区域，观察了不同Braak阶段的人脑中tau的种子水平。不仅在受病理影响的大脑区域检测到tau种子水平，而且在Braak通路上随后的非病理区域也检测到了tau种子水平。这些数据表明，致病的tau聚集体先于明显的tau病理，其方式与tau聚集体的跨神经元扩散是一致的。然后，我们在额叶白质束和视神经中检测到tau的种子，这两个大脑区域由轴突组成，含有很少或没有神经元细胞体，这意味着tau聚集体确实可以沿着轴突移动。最后，我们从不同Braak分期的大脑中分离出Braak Tau通路上的胞浆和突触体组分。磷酸化和种子活性的tau显著富含在没有广泛细胞tau病理的大脑区域的突触部分，进一步表明聚集的tau种子沿着突触连接的神经元在人脑中移动。总之，这些数据提供了进一步的证据，证明tau聚集体沿着突触连接的网络通过人脑传播导致人类阿尔茨海默病的发病机制。
Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate—i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau—, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.
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影响因子：
5.3
作者：
Castillo-Carranza, Diana L.;Sengupta, Urmi;Kayed, Rakez
通讯作者：
Kayed, Rakez
影响因子：
1.2
作者：
Furman, Jennifer L.;Holmes, Brandon B.;Diamond, Marc I.
通讯作者：
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影响因子：
2.5
作者：
Garcia-Marin, V.;Blazquez-Llorca, L.;DeFelipe, J.
通讯作者：
DeFelipe, J.
影响因子：
2.9
作者：
BLANKS, JC;HINTON, DR;MILLER, CA
通讯作者：
MILLER, CA
影响因子：
8.8
作者：
Calafate, Sara;Buist, Arjan;Moechars, Diederik
通讯作者：
Moechars, Diederik