Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College, London WC1N 1PJ, UK.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, S-43180 Molndal, Sweden.
Cells. 2021 Oct 24;10(11):2866. doi: 10.3390/cells10112866.
Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of are associated with an increased risk of developing dementia. We investigated the influence of the Alzheimer's disease risk variant, R47H, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47H iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47H variant may underlie the increased risk of Alzheimer's disease associated with this variant.
小胶质细胞外泌体是一种新兴的通讯途径，参与完成小胶质细胞的稳态功能，并传递神经退行性信号。 基因变体 与痴呆风险增加相关。 我们研究了阿尔茨海默病风险变异体 R47H 对由人诱导多能干细胞（iPS）衍生的小胶质细胞（iPS-Mg）分泌的 3019 种蛋白质组成的小胶质细胞外泌体蛋白质组的影响。 根据 iPS-Mg 受到的刺激，外泌体蛋白含量发生变化。 因此，脂多糖（LPS）诱导小胶质细胞外泌体包含更多的炎症信号，而 TREM2 配体磷脂酰丝氨酸（PS）的刺激则增加了小胶质细胞外泌体中的代谢信号。 我们测试了这些外泌体对神经元的影响，发现外泌体蛋白变化具有功能相关性，并影响神经元和小胶质细胞中的下游功能。 与来自常见 变体 iPS-Mg 的外泌体相比，来自 R47H iPS-Mg 的外泌体包含与疾病相关的小胶质细胞（DAM）特征蛋白，并且在促进神经元突起的生长和增加神经元中线粒体代谢方面的能力较弱。 总之，这些数据强调了小胶质细胞外泌体在完成小胶质细胞功能方面的重要性。 此外，由 R47H 变体影响的外泌体蛋白质组的变化可能是该变体与阿尔茨海默病风险增加相关的基础。
