星形胶质细胞和小胶质细胞之间的串扰导致 α-突触核蛋白和淀粉样-β 聚集物的降解增加。

Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates.

机构信息

Molecular Geriatrics, Rudbeck Laboratory, Department of Public Health & Caring Sciences/, Uppsala University, Uppsala, Sweden.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.

出版信息

J Neuroinflammation. 2021 Jun 3;18(1):124. doi: 10.1186/s12974-021-02158-3.

DOI:10.1186/s12974-021-02158-3

PMID:34082772

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8173980/

Abstract

BACKGROUND

Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.

METHODS

The aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized "close-culture" chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.

RESULTS

Our data show that intracellular deposits of αSYN and Aβ are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the "close-culture" chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.

CONCLUSIONS

Taken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.

摘要

背景

阿尔茨海默病（AD）和帕金森病（PD）的特征分别是大脑中聚集的淀粉样β（Aβ）和α-突触核蛋白（αSYN）的积累。为了开发有效的治疗方法，了解 Aβ/αSYN 聚集物如何被清除至关重要。令人信服的数据表明，神经炎性细胞，包括星形胶质细胞和小胶质细胞，在 AD 和 PD 的发病机制中发挥着核心作用。然而，这两种细胞类型之间的相互作用如何影响它们的清除能力，进而影响疾病的进展尚不清楚。

方法

本研究旨在探讨神经胶质细胞间的相互作用如何影响 αSYN 和 Aβ 病理学，重点关注其积累和降解。为此，我们用超声处理的 αSYN 或 Aβ 纤维来刺激人诱导多能干细胞（hiPSC）衍生的星形胶质细胞和小胶质细胞，并在不同时间点进行分析。我们通过免疫细胞化学和 ELISA 研究了这两种细胞类型在单独培养或共培养时清除细胞外和细胞内蛋白聚集体的能力。此外，我们还使用延时显微镜和定制的“近培养”腔追踪细胞与蛋白聚集体相互作用和处理蛋白聚集体的能力，在该腔中，星形胶质细胞和小胶质细胞的贴壁表面通过<1mm 的空间分隔开。

结果

我们的数据表明，与星形胶质细胞或小胶质细胞的单独培养相比，星形胶质细胞和小胶质细胞的共培养显著减少了细胞内 αSYN 和 Aβ 的沉积。对条件培养基的分析和“近培养”腔实验的成像数据表明，星形胶质细胞分泌了其内化蛋白聚集体的很大一部分，而小胶质细胞则没有。此外，共培养的星形胶质细胞和小胶质细胞通过隧道纳米管和其他膜结构彼此保持持续接触。值得注意的是，我们的活细胞成像数据表明，当小胶质细胞附着在星形胶质细胞膜上时，它可以吸引并清除星形胶质细胞内的细胞内蛋白沉积物。