Does proteopathic tau propagate trans-synaptically in the brain?,Molecular Neurodegeneration

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Does proteopathic tau propagate trans-synaptically in the brain?
Molecular Neurodegeneration ( IF 15.1 ) Pub Date : 2022-03-16 , DOI: 10.1186/s13024-022-00527-x
Wen Hu ₁ , Fei Liu ₁ , Cheng-Xin Gong ₁ , Khalid Iqbal ₁

Affiliation

Neurofibrillary pathology comprising hyperphosphorylated tau is one of the two hallmarks that characterize Alzheimer’s disease (AD) histopathologically, and it is clinically correlated with, and predicts the severity of, cognitive deficits in AD. The spread of tau pathology within AD brain follows a stereotypical pattern, from the trans-entorhinal region to the limbic system and eventually to the primary cortical areas. This hierarchical pattern suggests that tau pathology is transmitted from one area of the brain to other regions via anatomical connection [1].

The transmission of tau pathology is attributed to the propagation of seeding-competent/proteopathic tau from neuron to neuron and the resultant prion-like templated aggregation in the recipient cell. Several hypotheses explain how proteopathic tau spreads from one brain region to another. The most popular one is the trans-synaptic hypothesis, proposing that proteopathic tau propagates via the synapse in an anterograde fashion [2,3,4]. However, a comprehensive histopathological study of postmortem human brains showed that the progression of dendritic tau lesions in the temporal allocortex appeared to follow a direction opposite to currently known unidirectional hippocampal connectivity despite that rare or unknown projections might be involved [5]. Does proteopathic tau propagate trans-synaptically in the brain?

The trans-synaptic hypothesis initially proposed was based on studies using bigenic neuropsin-tTA-tau mice [2, 3]. The bigenic model was generated by crossing two existing mouse lines, the neuropsin-tTA transactivator line (the tTA-EC line) and the Tg(tetO-tau_P301L)4510 responder line. In this bigenic model, the aggregation-prone, P301L-mutated human tau was expressed predominantly in the superficial layers of the medial entorhinal cortex (EC) and pre−/para-subiculum. It appeared to take several months for somatodendritic tau pathology to progress from the EC to the granule cell layer of dentate gyrus (GrDG), a hippocampal subfield that is known to unidirectionally receive axonal inputs from the EC.

Intriguingly, the removal of endogenous mouse tau in the bigenic neuropsin-tTA-tau model did not appear to affect EC-GrDG tau “propagation” [6]. This finding suggests that late-onset tau pathology in the GrDG was a consequence of accumulation of “propagated” tau from the EC if, indeed, propagation did occur. It also suggests that no prion-like mechanism was involved. Another possibility could be that tau propagation did not occur in this model. Indeed, the responder line itself exhibited a certain level of “leaky” expression of human tau in the dentate gyrus in the absence of tTA transgene [7]. In addition, a detailed brain-wide survey of the distribution of the tTA transgene in the tTA-EC activator line revealed that tTA expression was not inherently restricted to the EC but instead distributed in a broad fashion; a subset of DG granule cells also exhibited appreciable levels of tTA [8]. Therefore, the delayed development of somatodendritic tau pathology in the GrDG in neuropsin-tTA-tau mice could result from low expression of human tau independently of tau propagation, because the expression level of aggregation-prone tau predicts the rate of development of tau pathology. Thus, data from the neuropsin-tTA-tau mouse model are not sufficient to substantiate a definite conclusion of trans-synaptic tau propagation.

A model that is more disease-relevant and persuasive in testing trans-synaptic tau propagation is the in vivo tau inoculation model, in which tau pathology is induced and characterized in the mouse brain by injection of proteopathic tau. Although neuronal connectivity-based propagation was consistently observed [9,10,11,12,13] and inter-neuronal tau propagation was thought to occur in some inoculation studies, detailed analyses of the representative data do not appear to support the trans-synaptic hypothesis [9,10,11, 14]. First, up to 11 months after tau inoculation in the hippocampus, somatodendritic tau pathology was induced locally and in axonally connected upstream (afferent) regions, including the superficial layers of the EC [9, 15] and the medial septal nucleus [11]; only axonal/neuritic—no somatodendritic—tau accumulation was seen in distant regions that are exclusively or predominantly downstream (efferent) to the hippocampus, including the deep layers of the EC [9], the lateral septal nucleus [9, 11] and the contralateral hippocampal CA1 subfield [11] (Fig. 1A). Second, detailed surveys of tau pathology in the whole brain after tau inoculation in non-transgenic mice and computational modeling showed that pathological tau mostly underwent retrograde propagation to distant regions according to known brain connectivity [10, 11, 15]. Third, tau inoculation in the hippocampus consistently induced tau pathology in the locus coeruleus within 2 weeks in young adult PS19 (tau_P301S) mice; in contrast, tau inoculation in the locus coeruleus failed to induce tau pathology in the hippocampus, even after incubation for 6 months under experimental conditions that were otherwise identical [14] (Fig. 1B). Locus coeruleus is a pontine nucleus that projects axons to, but does not receive axonal inputs from, the hippocampus. Therefore, there is no evidence of secondary seeding due to trans-synaptic propagation of tau from the hippocampus to EC deep layers or from the locus coeruleus to the hippocampus. Taken together, the in vivo tau inoculation studies suggest axonal uptake of injected tau and primary seeding in distant brain regions, but they do not support trans-synaptic tau propagation (Fig. 1C).

The synapse is an inter-neuronal contact area that is highly specialized for the flow, and its modulation, of neural signals between neurons. Other than neurotransmitters and neuromodulators, only a few neurophilic viruses and toxins are known to undergo trans-synaptic transmission. As a microtubule-associated protein that functions primarily to stimulate the assembly of, and help stabilize, microtubules, tau is thought to undergo axonal sorting and to be mainly localized in the axonal compartment of mature neurons under physiological conditions. Tau is also thought to be mis-localized and aggregated in the somatodendritic compartment under pathological conditions. Although tau is found at the pre- and post-synaptic compartments, it remains uncertain whether and how seeding-competent tau species, if generated somatodendritically, are transported anterogradely in the axon and released to the synaptic cleft.

Although the absence of convincing evidence does not exclude the possibility of trans-synaptic tau propagation, based on the experimental data accumulated so far, whether proteopathic tau propagates trans-synaptically in vivo remains a question, and a definite conclusion remains to be substantiated in future studies. Whereas tau gene delivery supplemented with 2A self-cleaving peptides has emerged as an attractive tool in differentiating donor and recipient neurons in the context of inter-neuronal tau transfer [6], the specificity of the technique remains to be validated. An ideal model to test trans-synaptic tau propagation would be intracerebral tau inoculation that targets a well-established unidirectional circuit in rodents and is free from confounding by endogenous tau load. The key determinant for a successful inoculation model is the precision injection of a small volume (10-100 nl, for instance) of proteopathic tau that is truly restricted to the target area, as was done in the early tract-tracing studies. Pressure injection of a large volume in the brain parenchyma can be problematic because of off-targeting of neurons that are irrelevant to the circuit of interest. In tau inoculation, simultaneous tracing with suitable neuronal tracers that exhibit labeling stability and minimal neural toxicity can be informative for better interpretation of data.

It takes years for tau pathology to progress to a higher Braak stage in the human brain. If trans-synaptic tau propagation does occur in the tau inoculation mouse model, it should involve the generation of secondary proteopathic tau in the neurons that have internalized the injected, primary seeds, and involve the extracellular release of the secondary seeds at the synapse and in turn the uptake of these seeds by synaptically connected neurons. In this regard, the incubation period should be substantially longer than primary seeding. Although transgenic mice overexpressing aggregation-prone mutated tau may enable rapid tau seeding, the transgene expression can be uneven in the brain, and the varying levels of expression should be carefully considered in interpreting inoculation studies [12, 14].

Inspired by the Braak staging of tau pathology, the conceptual evolution from intraneuronal accumulation of tau filaments to a more dynamic process that involves inter-neuronal trafficking of proteopathic tau via the extracellular space has pinpointed tau as a promising therapeutic target. Mechanistic insights into how AD tau pathology progresses would help guide the development of therapeutic strategies. Future studies are needed to ascertain whether proteopathic tau propagates trans-synaptically in a commonly thought anterograde, or possibly retrograde, fashion in the brain, and to unravel the mechanisms underlying the stereotypical pattern of tau pathology progression.

Not applicable.

AD:: Alzheimer’s disease
EC:: Entorhinal cortex
GrDG:: Granule cell layer of dentate gyrus
tTA:: Tetracycline transactivator

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We thank Ms. Maureen Marlow of our institute for language editing.

This work was supported by funds from the New York State Office for People With Developmental Disabilities.

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Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA
Wen Hu, Fei Liu, Cheng-Xin Gong & Khalid Iqbal

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WH conceived the study and wrote manuscript. FL, CXG and KI critically reviewed the manuscript with significant inputs. The author(s) read and approved the final manuscript.

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Hu, W., Liu, F., Gong, CX. et al. Does proteopathic tau propagate trans-synaptically in the brain?. Mol Neurodegeneration 17, 21 (2022). https://doi.org/10.1186/s13024-022-00527-x

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Received: 22 December 2021
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DOI: https://doi.org/10.1186/s13024-022-00527-x

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中文翻译：

proteopathic tau 是否在大脑中跨突触传播？

包含过度磷酸化 tau 的神经原纤维病理学是在组织病理学上表征阿尔茨海默病 (AD) 的两个标志之一，它在临床上与 AD 中的认知缺陷相关并预测其严重程度。AD 脑内 tau 病理学的传播遵循一种刻板的模式，从跨内嗅区到边缘系统，最终到初级皮层区域。这种分层模式表明 tau 病理通过解剖连接从大脑的一个区域传播到其他区域 [1]。

tau 病理学的传播归因于播种能力/蛋白病 tau 从神经元到神经元的传播以及在受体细胞中产生的朊病毒样模板聚集。几个假设解释了蛋白病 tau 如何从一个大脑区域传播到另一个大脑区域。最流行的一种是跨突触假说，它提出了 proteopathic tau 以顺行方式通过突触传播 [2,3,4]。然而，一项对死后人脑的全面组织病理学研究表明，尽管可能涉及罕见或未知的预测，但颞叶皮质中树突状 tau 病变的进展似乎遵循与目前已知的单向海马连接相反的方向 [5]。proteopathic tau 是否在大脑中跨突触传播？

最初提出的跨突触假说是基于使用生物神经蛋白-tTA-tau 小鼠的研究 [2, 3]。通过交叉两个现有的小鼠品系，神经蛋白-tTA 反式激活剂系（tTA-EC 系）和 Tg(tetO-tau _P301L )4510 响应系，生成了 bigenic 模型。在这个生物模型中，易于聚集的 P301L 突变的人类 tau 主要在内侧内嗅皮层 (EC) 和前/副下颌骨的表层中表达。体树突状 tau 病理学似乎需要几个月的时间才能从 EC 发展到齿状回 (GrDG) 的颗粒细胞层，这是一个已知单向接收来自 EC 的轴突输入的海马亚区。

有趣的是，在生物神经蛋白-tTA-tau 模型中去除内源性小鼠 tau 似乎并未影响 EC-GrDG tau“传播”[6]。这一发现表明，如果确实发生了传播，GrDG 中的迟发性 tau 病理学是来自 EC 的“传播的”tau 积累的结果。它还表明不涉及朊病毒样机制。另一种可能性可能是该模型中没有发生 tau 传播。事实上，在没有 tTA 转基因的情况下，响应系本身在齿状回中表现出一定水平的人 tau 表达“泄漏”[7]。此外，对 tTA-EC 激活剂系中 tTA 转基因分布的详细全脑调查显示，tTA 表达并非天生局限于 EC，而是以广泛的方式分布。DG 颗粒细胞的一个子集也表现出可观的 tTA [8] 水平。因此，神经蛋白-tTA-tau 小鼠 GrDG 中体树突 tau 病理学的延迟发展可能是由于人 tau 的低表达与 tau 传播无关，因为易聚集的 tau 的表达水平预测了 tau 病理学的发展速度。因此，来自神经蛋白-tTA-tau 小鼠模型的数据不足以证实跨突触 tau 传播的明确结论。

在测试跨突触 tau 传播时更与疾病相关和有说服力的模型是体内 tau 接种模型，其中通过注射蛋白病 tau 在小鼠大脑中诱导和表征 tau 病理学。尽管始终观察到基于神经元连接的传播 [9,10,11,12,13] 并且在一些接种研究中认为神经元间 tau 传播发生，但对代表性数据的详细分析似乎不支持跨突触假设 [9,10,11, 14]。首先，在海马中接种 tau 后长达 11 个月，在局部和轴突连接的上游（传入）区域（包括 EC 的浅层 [9, 15] 和内侧间隔核 [11]）诱导了体树突状 tau 病理学；在仅或主要位于海马下游（传出）的远处区域，包括 EC 的深层 [9]、侧隔核 [9, 11] 和对侧海马 CA1 亚区 [11]（图 1A）。其次，对非转基因小鼠接种 tau 后全脑 tau 病理学的详细调查和计算模型表明，根据已知的大脑连通性，病理性 tau 主要经历逆行传播到远处区域 [10, 11, 15]。第三，海马中的 tau 接种在年轻成人 PS19（tau 侧隔核 [9, 11] 和对侧海马 CA1 亚区 [11]（图 1A）。其次，对非转基因小鼠接种 tau 后全脑 tau 病理学的详细调查和计算模型表明，根据已知的大脑连通性，病理性 tau 主要经历逆行传播到远处区域 [10, 11, 15]。第三，海马中的 tau 接种在年轻成人 PS19（tau 侧隔核 [9, 11] 和对侧海马 CA1 亚区 [11]（图 1A）。其次，对非转基因小鼠接种 tau 后全脑 tau 病理学的详细调查和计算模型表明，根据已知的大脑连通性，病理性 tau 主要经历逆行传播到远处区域 [10, 11, 15]。第三，海马中的 tau 接种在年轻成人 PS19（tau 对非转基因小鼠接种 tau 后全脑 tau 病理学的详细调查和计算模型表明，根据已知的大脑连通性，病理性 tau 主要经历逆行传播到远处区域 [10, 11, 15]。第三，海马中的 tau 接种在年轻成人 PS19（tau 对非转基因小鼠接种 tau 后全脑 tau 病理学的详细调查和计算模型表明，根据已知的大脑连接，病理性 tau 主要经历逆行传播到远处区域 [10, 11, 15]。第三，海马中的 tau 接种在年轻成人 PS19（tau_P301S ) 小鼠；相比之下，即使在其他相同的实验条件下孵育 6 个月后，蓝斑中的 tau 接种未能在海马中诱导 tau 病理学[14]（图 1B）。蓝斑是一个脑桥核，将轴突投射到海马体，但不接收来自海马体的轴突输入。因此，没有证据表明由于 tau 从海马到 EC 深层或从蓝斑到海马的跨突触传播而导致二次播种。总之，体内 tau 接种研究表明，注射 tau 的轴突摄取和远距离大脑区域的初级播种，但它们不支持跨突触 tau 传播（图 1C）。

突触是神经元间的接触区域，高度专门用于神经元之间神经信号的流动及其调制。除了神经递质和神经调节剂，已知只有少数嗜神经病毒和毒素会发生跨突触传递。作为一种微管相关蛋白，其主要功能是刺激微管的组装并帮助稳定微管，tau 被认为会进行轴突分选，并且在生理条件下主要定位于成熟神经元的轴突区室。Tau 也被认为在病理条件下错误定位和聚集在体树突区室中。虽然 tau 存在于突触前和突触后区室，但仍不确定具有播种能力的 tau 物种是否以及如何产生，如果以体树突方式产生，

虽然缺乏令人信服的证据并不排除 tau 跨突触传播的可能性，但基于目前积累的实验数据，proteopathic tau 是否在体内跨突触传播仍然是一个问题，明确的结论有待未来证实学习。虽然 tau 基因递送辅以 2A 自切割肽已成为在神经元间 tau 转移的背景下区分供体和受体神经元的有吸引力的工具 [6]，但该技术的特异性仍有待验证。测试跨突触 tau 传播的理想模型是脑内 tau 接种，该接种针对啮齿动物中成熟的单向回路，并且不受内源性 tau 负载的混淆。成功接种模型的关键决定因素是精确注射小体积（例如 10-100 nl）的蛋白质 tau，该 tau 真正限制在目标区域，正如早期的追踪研究所做的那样。由于与感兴趣的电路无关的神经元的脱靶，在脑实质中进行大量压力注射可能会出现问题。在 tau 接种中，与表现出标记稳定性和最小神经毒性的合适的神经元示踪剂同时追踪可以为更好地解释数据提供信息。由于与感兴趣的电路无关的神经元的脱靶，在脑实质中进行大量压力注射可能会出现问题。在 tau 接种中，与表现出标记稳定性和最小神经毒性的合适的神经元示踪剂同时追踪可以为更好地解释数据提供信息。由于与感兴趣的电路无关的神经元的脱靶，在脑实质中进行大量压力注射可能会出现问题。在 tau 接种中，与表现出标记稳定性和最小神经毒性的合适的神经元示踪剂同时追踪可以为更好地解释数据提供信息。

tau 病理学需要数年时间才能在人脑中发展到更高的 Braak 阶段。如果在 tau 接种小鼠模型中确实发生了跨突触 tau 传播，它应该涉及在已内化注射的初级种子的神经元中产生次级蛋白病性 tau，并涉及在突触和在细胞外释放次级种子。通过突触连接的神经元来吸收这些种子。在这方面，潜伏期应比初播长得多。尽管过度表达易聚集突变 tau 的转基因小鼠可以实现快速 tau 播种，但转基因在大脑中的表达可能不均匀，在解释接种研究时应仔细考虑不同的表达水平 [12, 14]。

受 tau 病理学 Braak 分期的启发，从 tau 细丝的神经元内积累到更动态的过程的概念演变，包括通过细胞外空间在神经元间运输蛋白病 tau，已将 tau 确定为有前途的治疗靶点。对 AD tau 病理学进展的机制见解将有助于指导治疗策略的发展。未来的研究需要确定蛋白病 tau 是否以通常认为的顺行或逆行方式在大脑中跨突触传播，并揭示 tau 病理进展的刻板模式背后的机制。

不适用。

广告：: 阿尔茨海默氏病
欧共体：: 内嗅皮层
GrDG：: 齿状回颗粒细胞层
时间：: 四环素反式激活剂

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我们感谢我们研究所的 Maureen Marlow 女士的语言编辑。

这项工作得到了纽约州发育障碍人士办公室的资金支持。

隶属关系

纽约州发育障碍基础研究所 Inge Grundke-Iqbal 研究室神经化学系，美国纽约史泰登岛
Wen Hu, Fei Liu, Cheng-Xin Gong & Khalid Iqbal

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WH 构思了这项研究并撰写了手稿。FL、CXG 和 KI 认真审查了手稿，并提供了大量投入。作者阅读并批准了最终手稿。

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