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Cited by 45Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation

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Marino, Claudia, Perez‐Corredor, Paula, O'Hare, Michael, Heuer, Annie, Chmielewska, Natalia, Gordon, Harper, Chandrahas, Anita S., Gonzalez‐Buendia, Lucia +14 more·2024·Alzheimer's & Dementia
DOI 10.1002/alz.13436PMC PMC10916992
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Abstract

INTRODUCTION: We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs). METHODS: We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE‐HSPG interactions. RESULTS: We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin‐ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE‐induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock‐in mice. Targeting ApoE‐HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.

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  • Marino et al. developed an APOE3 Christchurch-inspired antibody to disrupt APOE4-HSPG interactions, resulting in reduced tau pathology in P301S mouse retinas and brains.

    “Marino et al. developed an APOE3 Christchurch-inspired antibody to disrupt APOE4-HSPG interactions, resulting in reduced tau pathology in P301S mouse retinas and brains66.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [66]

    The Results report that the Christchurch-mimetic 7C11 antibody reduced ApoE3-induced tau pathology in P301S mouse retinas. They also report reduced brain tau phosphorylation, but that experiment used APOE4 knock-in mice, not P301S mice (Results, Figures 4–5; page numbers unavailable). (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Marino et al. developed an APOE3 Christchurch-inspired antibody to disrupt human APOE4-HSPG interactions, resulting in reduced tau pathology in the retinas and brains of P301S mice.

    “Marino et al. developed an APOE3 Christchurch-inspired antibody to disrupt human APOE4-HSPG interactions, resulting in reduced tau pathology in the retinas and brains of P301S mice62.”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [62]

    The Results (Figure 4E–G; page unavailable) report that the Christchurch-mimetic antibody reduced ApoE3-induced tau phosphorylation in P301S mouse retinas. The paper explicitly says that retinal model did not assess brain changes; reduced brain tau phosphorylation was measured separately in APOE4 knock-in mice (Results, Figure 5; page unavailable). Thus the claim incorrectly places both the brain result and the APOE4 result in P301S mice. (LLM, conf=0.93)

    Experimental — accuracy not yet measured

  • An APOE Christchurch-mimetic antibody that disrupts APOE-heparin binding has shown promise in reducing tau hyperphosphorylation in mouse models of tauopathy.

    “an APOE Christchurch-mimetic antibody that disrupts APOE–heparin binding has shown promise in reducing tau hyperphosphorylation in mouse models of tauopathy199.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [199]

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Authors
Marino, C., Perez‐Corredor, P., O'Hare, M., Heuer, A., Chmielewska, N., Gordon, H., Chandrahas, A. S., Gonzalez‐Buendia, L., Delgado‐Tirado, S., Doan, T. H., Vanderleest, T. E., Arevalo‐Alquichire, S., Obar, R. A., Ortiz‐Cordero, C., Villegas, A., Sepulveda‐Falla, D., Kim, L. A., Lopera, F., Mahley, R., Huang, Y., Quiroz, Y. T., & Arboleda‐Velasquez, J. F.
Affiliations
  • Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology at Harvard Medical School Boston Massachusetts USA
  • Massachusetts Eye and Ear Infirmary (US)
  • Harvard University (US)
  • Massachusetts Institute of Technology (US)
  • Grupo de Neurociencias de Antioquia, Facultad de Medicina Universidad de Antioquia Medellín Colombia
  • Molecular Neuropathology of Alzheimer's Disease Institute of Neuropathology University Medical Center Hamburg‐Eppendorf Hamburg Germany
  • Universidad de Antioquia (CO)
  • Gladstone Institutes (US)
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2023-10-04
Volume
20
Issue
2
Pages
819-836
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.13436
PMC
PMC10916992
OpenAlex
W4387326153
Cited by
45
References
51
Citations by year
2026: 10 · 2025: 18 · 2024: 15 · 2023: 2
FWCI
7.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Greater South Information System
Funders
  • Alzheimer's Association
  • Massachusetts General Hospital
  • Edward N. and Della L. Thome Memorial Foundation
  • Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
  • Open Philanthropy Project
  • Good Ventures Foundation
  • National Institutes of Health (DP5OD019833)
  • National Institute on Aging (R01AG054671, RF1AG077627)
  • National Eye Institute (P30EY003790)
  • National Institute of Neurological Disorders and Stroke (RF1NS110048, UH3NS100121)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Humans, Immunologic Factors, Phosphorylation, Heparan Sulfate Proteoglycans, Mice, Apolipoprotein E3, Apolipoprotein E4

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