A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models
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Published:2023-01-12
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ISSN:1097-6256
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Container-title:Nature Neuroscience
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language:en
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Short-container-title:Nat Neurosci
Author:
van Lengerich Bettina, Zhan LihongORCID, Xia Dan, Chan Darren, Joy DavidORCID, Park Joshua I., Tatarakis David, Calvert Meredith, Hummel Selina, Lianoglou SteveORCID, 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, Gnörich Johannes, Ha Connie, Kannuswamy Malavika, Kim Do Jin, Kunte Sebastian T., Kunze Lea H.ORCID, Lac Diana, Lechtenberg Kendra, Leung Amy Wing-Sze, Liang Chun-Chi, Lopez Isabel, McQuade Paul, Modi Anuja, Torres Vanessa O., Nguyen Hoang N.ORCID, Pesämaa 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 KenORCID, Zuchero Y. Joy Yu, Diaz Dolo, Dennis Mark S., Huang Fen, Scearce-Levie KimberlyORCID, Watts Ryan J., Haass ChristianORCID, Lewcock Joseph W., Di Paolo GilbertORCID, Brendel MatthiasORCID, Sanchez Pascal E.ORCID, Monroe Kathryn M.ORCID
Abstract
AbstractLoss-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.
Publisher
Springer Science and Business Media LLC
Subject
General Neuroscience
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