MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Neuron. 2012 Feb 23;73(4):685-97. doi: 10.1016/j.neuron.2011.11.033.
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.
神经原纤维缠结从阿尔茨海默病发展的内嗅皮层（EC-II）的 II 层向边缘和联合皮层推进。然而，涉及这种疾病进展的层次模式的机制尚不清楚。我们描述了一种转基因小鼠模型，其中人 tau P301L 的过表达仅限于 EC-II。tau 病理学从 EC 转基因表达神经元进展到没有可检测到的转基因表达的神经元，首先是 EC 邻近细胞，然后传播到突触回路中的下游神经元，如齿状回、海马 CA 区和扣带回。人 tau 蛋白传播到这些区域并与内源性小鼠 tau 共聚集。随着年龄的增长，在靶区和 EC 神经元发生突触退化。这些数据表明，tau 蛋白的一系列渐进性错误折叠、基于电路的向新细胞群的转移以及去传入诱导的退化是 tau 诱导的神经退行性变过程的一部分。
