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Cited by 21Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer’s disease

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Chen, Guiqin, Wang, Mengmeng, Zhang, Zhentao, Hong, Dae Ki, Ahn, Eun Hee, Liu, Xia, Kang, Seong Su, Ye, Keqiang·2025·Neuron
DOI 10.1016/j.neuron.2024.12.015PMC PMC12376192
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Abstract

PSEN1 E280A carrier for the APOE3 Christchurch variant (R136S) is protected against Alzheimer's disease (AD) symptoms with a distinct anatomical pattern of Tau pathology. However, the molecular mechanism accounting for this protective effect remains incompletely understood. Here, we show that the ApoE3 R136S mutant strongly binds to Tau and reduces its uptake into neurons and microglia compared with ApoE3 wild type (WT), diminishing Tau fragmentation by asparagine endopeptidase (AEP), proinflammatory cytokines by Tau pre-formed fibrils (PFFs) or β-amyloid (Aβ), and neurotoxicity. Further, ApoE3 R136S demonstrates more robust effects in attenuating AEP activation and Tau PFF spreading in the brains of both 5xFAD and Tau P301S mice than in ApoE3 WT, leading to improved cognitive functions. Thus, our findings support the idea that ApoE3 R136S strongly binds Tau and decreases its cellular uptake, abrogating Tau pathology propagation in AD brains.

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  • The protective effects of Christchurch have been attributed to reduced HSPG binding, which limits ApoE-mediated tau uptake and propagation, and to suppression of microglial cGAS-STING signaling.

    “The protective effects of Christchurch have been attributed to reduced HSPG binding, which limits ApoE-mediated tau uptake and propagation, and to suppression of microglial cGAS-STING signaling (21,39,40).”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [40]

    The Discussion (page unavailable) says ApoE3 Christchurch has low heparin-binding ability, discusses HSPG-mediated tau uptake, and reports another study suggesting protection through downregulation of cGAS-STING-IFN signaling. The Results and Discussion also report reduced tau uptake and propagation with R136S. However, this paper does not establish that reduced HSPG binding causes the reduced tau uptake, or specify that the reported cGAS-STING suppression occurs in microglia. (LLM, conf=0.85)

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  • Previous in vitro studies reported decreased Aβ aggregation in the presence of recombinant APOE3Ch compared with APOE3.

    “This would align with previous in vitro studies reporting decreased Aβ aggregation in the presence of recombinant APOE3Ch compared with APOE3 [3, 24].”

    From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [24]

  • Mounting evidence from human-based, in vitro, and in vivo studies has linked APOE3Ch to reduction in tau pathology.

    “Mounting evidence from human-based, in vitro, and in vivo studies has linked APOE3Ch to reduction in tau pathology [3–7, 24, 26, 41, 42].”

    From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [24]

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Sorted by citations

Authors
Chen, G., Wang, M., Zhang, Z., Hong, D. K., Ahn, E. H., Liu, X., Kang, S. S., & Ye, K.
Affiliations
  • Emory University (US)
  • Chinese Academy of Sciences (CN)
  • Renmin Hospital of Wuhan University (CN)
  • Hallym University (KR)
Corresponding author
  • Kang, Seong Su
  • Ye, Keqiang
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2025-03
Volume
113
Issue
5
Pages
719-736.e5
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2024.12.015
PMC
PMC12376192
OpenAlex
W4406366927
Cited by
21
References
16
Citations by year
2026: 8 · 2025: 13
FWCI
13.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Natural Science Foundation of China (82350710222, 82471439)
  • National Institute of Neurological Disorders and Stroke (P30NS055077)
  • School of Medicine, Emory University
  • Georgia Clinical and Translational Science Alliance (UL1TR002378)
  • National Institutes of Health (UL1TR002378)
  • Shenzhen Science and Technology Innovation Committee (JCYJ20230807140806015, KQTD20221101093608028)
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
Alzheimer's disease, tau protein, neuroprotection, asparaginyl endopeptidase, tau propagation, microglia, neuroinflammation, 5xFAD mice, cognitive function, neurodegeneration
MeSH terms
Alzheimer Disease, Animals, Brain, Cysteine Endopeptidases, Disease Models, Animal, Humans, Mice, Transgenic, Nerve Degeneration, Neurons, Protein Binding, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Apolipoprotein E3, Presenilin-1

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