Axon Neuroscience R & D Services SE, Bratislava, Slovakia.
Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
J Alzheimers Dis. 2020;77(2):551-568. doi: 10.3233/JAD-200047.
Neuronal accumulation of hyperphosphorylated and truncated tau aggregates is one of the major defining factors and key drivers of neurodegeneration in Alzheimer's disease and other tauopathies.
We developed an AAV-induced model of tauopathy mediated by human truncated tau protein without familial frontotemporal dementia-related mutations to study tau propagation and the functional consequences of tau pathology.
We performed targeted transductions of the hippocampus or entorhinal cortex in adult mice followed by histological analysis to study the progression of hippocampal tau pathology and tau spreading. We performed behavioral analysis of mice with AAV-induced hippocampal tau pathology.
AAV-induced hippocampal tau pathology was characterized by tau hyperphosphorylation (AT8 positivity), sarkosyl insolubility, and the presence of neurofibrillary tangles. AAV-induced tau pathology was associated with microgliosis and hypertrophic astrocytes in the absence of cognitive deficits. Additionally, the co-expression of mCherry fluorescent protein and human truncated tau enabled us to detect both local spreading of human tau and spreading from the entorhinal cortex to the synaptically connected dentate gyrus.
Targeted delivery of AAV with truncated tau protein into subcortical and cortical structures of mammalian brains represents an efficient approach for creating temporally and spatially well-defined tau pathology suitable for in vivo studies of tau propagation and neuronal circuit deficits in Alzheimer's disease.
神经元中过度磷酸化和截断的 tau 聚集体的积累是阿尔茨海默病和其他 tau 病中神经退行性变的主要定义因素和关键驱动因素之一。
我们开发了一种由人类截断 tau 蛋白介导的 tau 病 AAV 诱导模型，该模型没有家族性额颞叶痴呆相关突变，用于研究 tau 的传播和 tau 病理学的功能后果。
我们对成年小鼠的海马体或内嗅皮层进行靶向转导，然后进行组织学分析，以研究海马 tau 病理学的进展和 tau 的传播。我们对 AAV 诱导的海马 tau 病理学小鼠进行了行为分析。
AAV 诱导的海马 tau 病理学的特征是 tau 过度磷酸化（AT8 阳性）、 Sarkosyl 不溶性和神经原纤维缠结的存在。AAV 诱导的 tau 病理学与小胶质细胞增生和肥大星形胶质细胞有关，但没有认知缺陷。此外，mCherry 荧光蛋白和人类截断 tau 的共表达使我们能够检测到人类 tau 的局部传播以及从内嗅皮层到突触连接的齿状回的传播。
将截断的 tau 蛋白的 AAV 靶向递送至哺乳动物大脑的皮质和皮质下结构，是一种创建时间和空间上明确的 tau 病理学的有效方法，适用于阿尔茨海默病中 tau 传播和神经元回路缺陷的体内研究。
