美国德纳利治疗公司Kathryn M. Monroe研究组提出，TREM2激活抗体与血脑屏障转运载体增强阿尔茨海默病(AD)模型中的小胶质细胞代谢。2023年1月12日出版的《自然—神经科学》发表了这项成果。

他们描述了一种高亲和力的人TREM2激活抗体工程与单价转铁蛋白受体(TfR)结合位点，称为抗体运输载体(ATV)，以促进血脑屏障转胞作用。在小鼠外周递送后，ATV:TREM2与标准抗TREM2抗体相比，显示出改善的大脑生物分布和增强的信号。在人诱导多能干细胞(iPSC)来源的小胶质细胞中，ATV:TREM2诱导增殖并改善线粒体代谢。单细胞RNA测序和形态测量显示，ATV:TREM2将小胶质细胞转移到代谢反应状态，这与淀粉样蛋白病理诱导的状态不同。在AD小鼠模型中，ATV:TREM2促进了大脑微胶质细胞活动和葡萄糖代谢。因此，ATV:TREM2代表了一种有前途的方法来改善小胶质细胞功能和治疗AD患者发现的脑代谢低下。

研究人员表示，TREM2的功能丧失变体与AD的风险增加有关，这表明激活这种先天性免疫受体可能是一种有用的治疗策略。

附：英文原文

Title: A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Author: van Lengerich, Bettina, Zhan, Lihong, Xia, Dan, Chan, Darren, Joy, David, Park, Joshua I., Tatarakis, David, Calvert, Meredith, Hummel, Selina, Lianoglou, Steve, Pizzo, Michelle E., Prorok, Rachel, Thomsen, Elliot, Bartos, Laura M., Beumers, Philipp, Capell, Anja, Davis, Sonnet S., de Weerd, Lis, Dugas, Jason C., Duque, Joseph, Earr, Timothy, Gadkar, Kapil, Giese, Tina, Gill, Audrey, Gnrich, Johannes, Ha, Connie, Kannuswamy, Malavika, Kim, Do Jin, Kunte, Sebastian T., Kunze, Lea H., Lac, Diana, Lechtenberg, Kendra, Leung, Amy Wing-Sze, Liang, Chun-Chi, Lopez, Isabel, McQuade, Paul, Modi, Anuja, Torres, Vanessa O., Nguyen, Hoang N., Pesmaa, Ida, Propson, Nicholas, Reich, Marvin, Robles-Colmenares, Yaneth, Schlepckow, Kai, Slemann, Luna, Solanoy, Hilda, Suh, Jung H., Thorne, Robert G., Vieira, Chandler, Wind-Mark, Karin, Xiong, Ken, Zuchero, Y. Joy Yu, Diaz, Dolo, Dennis, Mark S., Huang, Fen, Scearce-Levie, Kimberly, Watts, Ryan J., Haass, Christian, Lewcock, Joseph W., Di Paolo, Gilbert, Brendel, Matthias, Sanchez, Pascal E., Monroe, Kathryn M.

Issue&Volume: 2023-01-12

Abstract: Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

DOI: 10.1038/s41593-022-01240-0

Source: https://www.nature.com/articles/s41593-022-01240-0