PDF(Pubmed)
Abstract：
Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer\'s disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways.
摘要：
以成对螺旋丝形式的错误折叠的病理性tau蛋白(ptau)的广泛皮质积累是阿尔茨海默病的主要标志。在疾病进展的各个阶段ptau的亚细胞定位可能是涉及其传播的细胞机制的信息。这里,我们发现，在死后的人体组织（n=25例）中，几个不同的前部丘脑核内的ptau密度随疾病分期而增加，前背核（ADn）始终受影响最大。在ADN，ptau阳性元素已经存在于皮质前(Braak0)阶段。Tau病理学优先影响ADn中谷氨酸能神经元的钙视网膜蛋白表达亚群。在亚细胞水平,我们在ADn细胞体中检测到ptau免疫反应性，树突,并且在一种特殊类型的突触前终末中，表达囊泡谷氨酸转运体2（vGLUT2）并可能源自乳头体。含ptau的终端显示退化的迹象，包括内体/溶酶体细胞器。相比之下,皮质丘脑轴突末端缺乏ptau。数据表明在疾病发作时ADn中特定细胞群的参与。皮质下谷氨酸能突触前末端中ptau的存在支持有关tau的跨突触扩散选择性影响专门的轴突通路的假设。
