Catterson James H, Mouofo Edmond N, López De Toledo Soler Inés, Lean Gillian, Dlamini Stella, Liddell Phoebe, Voong Graham, Katsinelos Taxiarchis, Wang Yu-Chun, Schoovaerts Nils, Verstreken Patrik, Spires-Jones Tara L, Durrant Claire S
Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.
UK Dementia Research Institute, The University of Edinburgh, Edinburgh EH8 9XD, UK.
Brain Commun. 2024 Aug 8;6(4):fcae256. doi: 10.1093/braincomms/fcae256. eCollection 2024.
Alzheimer's disease is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of Alzheimer's disease is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models, and indirect evidence for tau spread via synapses has been observed in human Alzheimer's disease. Halting tau propagation is a promising therapeutic target for Alzheimer's disease; thus, a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau in . Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing four different human tau constructs in two distinct neuronal populations reveals a robust resistance in to the trans-synaptic spread of human tau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global human tau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.
阿尔茨海默病是老年人痴呆最常见的病因，促使人们为确定有效的干预新治疗靶点付出了巨大努力。阿尔茨海默病的标志性特征之一是由过度磷酸化的tau蛋白组成的神经原纤维缠结的形成，其在大脑中的逐渐扩散与神经元死亡相关。在小鼠模型中已观察到tau的跨突触传播，并且在人类阿尔茨海默病中也已观察到tau通过突触传播的间接证据。阻止tau传播是阿尔茨海默病一个有前景的治疗靶点；因此，一个可扩展的用于筛选tau传播调节剂的模型系统对该领域将非常有用。为此，我们试图在……中模拟人类tau的跨突触传播。利用跨Tango回路映射技术，我们研究了tau是否在突触连接的神经元之间传播。免疫组织化学和共聚焦成像用于寻找tau的传播。对在两个不同神经元群体中表达四种不同人类tau构建体的数百只果蝇进行检查发现，……对人类tau的跨突触传播具有强大的抗性。这种抗性在同时表达淀粉样β的品系中、在全局人类tau敲入以在下游神经元中提供人类tau模板的品系中以及在温度操纵下均持续存在。这些阴性数据对该领域很重要，因为我们确定在神经元亚群中表达人类tau不太可能用于进行筛选以找到减少tau跨突触传播的机制。在……中观察到的固有抗性可能作为一个有价值的线索，为未来研究中阻碍tau传播的策略提供见解。
