Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Barbara Sárkány, Csaba Dávid, Tibor Hortobágyi, Péter Gombás, Peter Somogyi, László Acsády, Tim J. Viney
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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.

Abstract Image

人类丘脑前部谷氨酸能亚细胞域中 tau 细丝的早期选择性定位
以成对螺旋丝形式存在的错误折叠的病理性 tau 蛋白(ptau)在大脑皮层的广泛堆积是阿尔茨海默病的一个主要特征。在疾病进展的不同阶段,ptau 的亚细胞定位很可能是其扩散的细胞机制的信息来源。在这里,我们发现在死后人体组织(n = 25 例)中,丘脑几个不同喙核内的 ptau 密度随疾病阶段而增加,其中前背核(ADn)始终是受影响最大的。在ADn中,ptau阳性成分在皮层前(Braak 0)阶段就已经存在。Tau病理学优先影响ADn中表达钙调蛋白的谷氨酸能神经元亚群。在亚细胞水平,我们在ADn细胞体、树突和一种特殊类型的突触前末梢中检测到了ptau免疫反应,这种突触前末梢表达囊泡型谷氨酸转运体2(vGLUT2),很可能源自乳突体。含ptau的突触末端显示出变性迹象,包括内膜/溶酶体细胞器。相比之下,皮质丘脑轴突末梢缺乏ptau。这些数据证明了ADn发病初期有特定的细胞群参与其中。在皮层下谷氨酸能突触前末端存在ptau支持了关于tau选择性地影响专门轴突通路的突触前扩散的假设。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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