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Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons.

阿尔茨海默病脑源性细胞外囊泡在中间神经元传播tau病理学。

  • 影响因子:7.52
  • DOI:10.1093/brain/awaa376
  • 作者列表:"Ruan Z","Pathak D","Venkatesan Kalavai S","Yoshii-Kitahara A","Muraoka S","Bhatt N","Takamatsu-Yukawa K","Hu J","Wang Y","Hersh S","Ericsson M","Gorantla S","Gendelman HE","Kayed R","Ikezu S","Luebke JI","Ikezu T
  • 发表时间:2021-02-12
Abstract

:Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer's disease, prodromal Alzheimer's disease, and non-demented control cases. Alzheimer's disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer's disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer's disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer's disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer's disease or prodromal Alzheimer's disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer's disease donor showed little tau pathology. Furthermore, Alzheimer's disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.

摘要

: 细胞外囊泡是高度可传播的,并且在tau病理的传播中发挥关键作用,尽管潜在的机制仍然难以捉摸。在这里,我们首次全面表征了从阿尔茨海默病、前驱阿尔茨海默病和非痴呆对照病例中分离的人脑源性细胞外囊泡的理化结构和致病功能。与通过斑点印迹和原子力显微镜测定的前驱阿尔茨海默病或对照细胞外囊泡相比,阿尔茨海默病细胞外囊泡在表位特异性tau寡聚体中显著富集。阿尔茨海默病细胞外囊泡比前驱阿尔茨海默病和体外控制细胞外囊泡更有效地被鼠皮质神经元内化,以及更有效地转移和错误折叠tau。引人注目的是,在18月龄C57BL/6小鼠的齿状回外分子层中接种阿尔茨海默病或前驱阿尔茨海默病细胞外囊泡,仅含300 pg的tau,结果4.5个月时,异常磷酸化的tau在整个海马区蓄积,而从对照细胞外囊泡接种等量的tau,来自同一阿尔茨海默病供体的分离的tau寡聚体或原纤维显示很少的tau病理学。此外,阿尔茨海默病细胞外囊泡在海马区诱导了内源性tau蛋白的错误折叠,包括寡聚形式和肌基不溶性形式。出乎意料的是,磷酸化tau主要积聚在谷氨酸脱羧酶67 (GAD67) gaba能中间神经元以及较小程度的谷氨酸受体2/3阳性兴奋性苔藓细胞中,显示出优先的细胞外囊泡介导的gaba能中间神经元tau的繁殖。CA1锥体细胞的全细胞膜片钳记录显示自发抑制性突触后电流的幅度显著降低。这伴随着CA1区锥体神经元周围的c-fos + GAD67 + 神经元和GAD67 + 神经元点的减少,证实了该区域的gaba能传递减少。我们的研究假设了tau在海马gaba能中间神经元通过脑源性细胞外囊泡扩散的新机制及其随后的神经元功能障碍。

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