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Cited by 233Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsBarrier Structure and Function Studies

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

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van Lengerich, Bettina, Zhan, Lihong, Xia, Dan, Chan, Darren, Joy, David, Park, Joshua I., Tatarakis, David, Calvert, Meredith +55 more·2023·Nature Neuroscience
DOI 10.1038/s41593-022-01240-0PMC PMC9991924
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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.

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  • Depletion of either TREM2 or PLCγ2 has previously been shown to increase lipid accumulation and impair mitochondrial respiration via suppression of lipid regulatory genes, including FABP5.

    “depletion of either TREM2 or PLCγ2 has previously been shown to increase lipid accumulation and impair mitochondrial respiration via the suppression of lipid regulatory genes, including FABP5 [6, 8, 61].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [8]

    The Results section reports impaired mitochondrial respiration in both TREM2-knockout and PLCG2-knockout microglia. It also describes lipid accumulation with TREM2 loss of function and a failure of antibody-induced triglyceride reduction in PLCG2-knockout cells. The passages do not establish that depletion of either gene increases lipid accumulation through suppression of lipid-regulatory genes, and they do not identify FABP5 as the mechanism. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Genetic depletion of either TREM2 or PLCγ2 impairs lipid processing and mitochondrial function in human iPSC-derived microglia.

    “Genetic depletion of either TREM2 or PLCγ2 similarly impairs lipid processing and mitochondrial function in human iPSC-derived microglia (iMGL) [6, 8].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [8]

  • The protective PLCγ2-P522R variant may exert similar beneficial effects on microglial functions as those previously reported with a TREM2-activating antibody in different AD disease models.

    “Thus, the protective PLCγ2-P522R variant may exert similar beneficial effects on the functions of microglia as those previously reported with a TREM2-activating antibody in different AD disease models [8].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [8]

  • These included TREM2 and GBA, driven by a GBA1 missense variant (rs2230288, p.Glu365Lys; MAF=0.83%) that colocalizes with PD and DLB risk (PP.H4>0.997).

    “These included TREM2, a protein well known for modulating immune function in AD (50), and glucocerebrosidase (GBA), driven by a GBA1 missense variant [rs2230288, p.Glu365Lys; minor allele frequency (MAF) = 0.83%] that colocalizes with PD and DLB risk (PP. H4 > 0.997; table S19 and fig. S12A).”

    From Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease (2026) · cites this paper as [50]

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Cited by

Sorted by citations

Authors
van Lengerich, B., Zhan, L., Xia, D., Chan, D., Joy, D., Park, J. I., Tatarakis, D., Calvert, M., Hummel, S., Lianoglou, S., Pizzo, M. E., Prorok, R., Thomsen, E., Bartos, L. M., Beumers, P., Capell, A., Davis, S. S., de Weerd, L., Dugas, J. C., Duque, J., Earr, T., Gadkar, K., Giese, T., Gill, A., Gnörich, J., Ha, C., Kannuswamy, M., Kim, D. J., Kunte, S. T., Kunze, L. H., Lac, D., Lechtenberg, K., Leung, A. W.-S., Liang, C.-C., Lopez, I., McQuade, P., Modi, A., Torres, V. O., Nguyen, H. N., Pesämaa, I., Propson, N., Reich, M., Robles-Colmenares, Y., Schlepckow, K., Slemann, L., Solanoy, H., Suh, J. H., Thorne, R. G., Vieira, C., Wind-Mark, K., Xiong, K., Zuchero, Y. J. Y., Diaz, D., Dennis, M. S., Huang, F., Scearce-Levie, K., Watts, R. J., Haass, C., Lewcock, J. W., Di Paolo, G., Brendel, M., Sanchez, P. E., & Monroe, K. M.
Affiliations
  • Denali Therapeutics (United States) (US)
  • German Center for Neurodegenerative Diseases (DE)
  • Ludwig-Maximilians-Universität München (DE)
Corresponding author
  • Sanchez, Pascal E.
  • Monroe, Kathryn M.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2023-01-12
Volume
26
Issue
3
Pages
416-429
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-022-01240-0
PMC
PMC9991924
OpenAlex
W4315707278
Cited by
233
References
31
Citations by year
2026: 35 · 2025: 83 · 2024: 78 · 2023: 37
FWCI
24.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, cc-by)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
TREM2, Alzheimer's disease, transferrin receptor, microglial metabolism, mitochondrial metabolism, microglial activation, brain hypometabolism, glucose metabolism, iPSC-derived microglia, amyloid pathology
MeSH terms
Alzheimer Disease, Animals, Antibodies, Blood-Brain Barrier, Brain, Disease Models, Animal, Humans, Membrane Glycoproteins, Receptors, Immunologic, Tissue Distribution, Microglia, Mice, Induced Pluripotent Stem Cells

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