TDP-43 pathology is associated with increased tau burdens and seeding.
TDP-43 pathology is associated with increased tau burdens and seeding.
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DOI：
10.1186/s13024-023-00653-0
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发表时间：
2023-09-30
影响因子：
15.1
通讯作者：
Thal, Dietmar Rudolf
中科院分区：
文献类型：
--
作者：
Tome, Sandra O.;Tsaka, Grigoria;Ronisz, Alicja;Ospitalieri, Simona;Gawor, Klara;Gomes, Luis Aragao;Otto, Markus;von Arnim, Christine A. F.;Van Damme, Philip;van den Bosch, Ludo;Ghebremedhin, Estifanos;Laureyssen, Celeste;Sleegers, Kristel;Vandenberghe, Rik;Rousseau, Frederic;Schymkowitz, Joost;Thal, Dietmar Rudolf
除了淀粉样蛋白-β斑块和含有过度磷酸化tau（p-tau）的神经纤维缠结（NFT）之外，大多数阿尔茨海默病（AD）病例还表现出边缘系统主导的年龄相关性TDP-43脑病神经病理学变化（LATE-NC）。LATE-NC的特征在于病理性TDP-43阳性的细胞质聚集体，并且与缺乏TDP-43病理性TDP-43：AD（LATE-NC-）的AD病例相比，与AD中更严重的临床结果相关。越来越多的证据表明，TDP-43和p-tau相互作用，并在AD发病过程中表现出病理协同作用。然而，尚未完全理解TDP-43的存在如何影响症状性AD中的p-tau聚集。在这项研究中，我们研究了TDP-43蛋白质病对p-tau病理学的影响，采用不同的方法：组织学，在人类死后队列（n = 98），以及功能上使用tau生物传感器细胞系和TDP-43 A315 T转基因小鼠。我们发现，与AD（LATE-NC-）病例和对照组相比，AD（LATE-NC+）与LATE-NC共病的AD病例具有增加的前角和/或NFT负担以及增加的p-tau 199脑水平。TDP-43病理学负荷也与Braak NFT分期相关。与对照和AD（LATE-NC-）处理的细胞相比，用来自AD（LATE-NC+）病例的肌氨酰不溶性脑源性匀浆处理的tau生物传感器细胞系显示出加剧的p-tau接种。同样，与其余实验组相比，注射AD（LATE-NC+）衍生提取物的TDP-43 A315 T小鼠也表现出更严重的海马种植，尽管未观察到TDP-43聚集。我们的研究结果通过支持TDP-43和p-tau之间的功能协同作用扩展了当前的知识。我们进一步证明，TDP-43病理学以间接方式抑制p-tau聚集，并可能通过增加p-tau水平来增加其接种潜力。这可能最终导致tau驱动的神经毒性和细胞死亡。由于大多数AD病例存在共病LATE-NC，因此本研究对AD和LATE中TDP-43和tau发病机制的理解产生了影响，这占全球大多数痴呆病例。此外，它强调需要开发一种生物标志物，在生活中检测TDP-43，以便正确地对AD和LATE患者进行分层。在线版本包含补充材料，可通过10.1186/s13024-023-00653-0获得。
Most Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43: AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD. In this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches: histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice. We found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed. Our findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients. The online version contains supplementary material available at 10.1186/s13024-023-00653-0.
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DOI：
10.1084/jem.20160833
发表时间：
2016-11-14
期刊：
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影响因子：
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影响因子：
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