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

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; Gnoerich, 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.; Pesaemaa, 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. und Monroe, Kathryn M. (2023): A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models. In: Nature Neuroscience, Bd. 26, Nr. 3: 416-+

Abstract

van Lengerich et al. developed a human TREM2 antibody with a transport vehicle (ATV) that improves brain exposure and biodistribution in mouse models. ATV:TREM2 promotes microglial energetic capacity and metabolism via mitochondrial pathways. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198