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Cited by 7Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease

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Perez‐Corredor, Paula, Arevalo‐Alquichire, Said, Mazzarino, Randall C., O'Hare, Michael, Muriel‐Torres, Andres F., Vacano, Guido N., Vanderleest, Timothy E., Miller, William P. +7 more·2025·Alzheimer's & Dementia
DOI 10.1002/alz.70396PMC PMC12242688
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Abstract

INTRODUCTION: We described a protected case with familial Alzheimer's disease, homozygous for apolipoprotein E3 (APOE3) Christchurch variant (ApoE3Ch), exhibiting low tau protein levels despite genetic predisposition to the disease due to presenilin (PSEN)1‐E280A. We reported the loss of interaction between ApoE3Ch and heparan sulfate proteoglycans (HSPGs) as a critical protective pathway. Here, we characterized differential interacting partners for both wild‐type and Christchurch variants to identify additional protective mechanisms of ApoE3Ch. METHODS: We performed pull‐down of mouse brain lysates using His‐tag‐ApoE3 recombinant proteins and determined interacting partners of ApoE3 via mass‐spectrometry. We then performed in vitro and in vivo assays to validate the top interactors. RESULTS: We found enhanced binding of ApoE3Ch to tau and Dickkopf‐1 (Dkk1, a WNT/β‐catenin antagonist) that resulted in reduced tau aggregation in vitro. We demonstrated that ApoE3Ch interacts directly with Dkk1 and tau, reducing tau pathology. These findings supported the hypothesis of novel protective effects of direct ApoE3Ch interactions. Highlights: ⁠Apolipoprotein E3 (ApoE3) Christchurch variant (ApoE3Ch) exhibits different protein interaction profiles compared to wild‐type ApoE3, as revealed by proteomic analyses and pull‐down experiments. The ApoE3Ch variant alters the protein's interaction with tau, thus affecting its aggregation in a tau biosensor cell assay and the retina of microtubule‐associated protein tau (MAPT*P301S) transgenic mice. ⁠Gene ontology and pathway analyses indicate that ApoE3Ch interactors are associated with brain‐related disorders and specific upstream regulators, including MAPT, a gene encoding for tau. ⁠Protein–protein interaction studies showed increased binding of ApoE3Ch to Dickkopf1 (Dkk1), a Wnt/β‐catenin pathway antagonist, as compared to ApoE3WT, thus indicating that multiple protective mechanisms are regulated by the ApoE3Ch variant Our study uncovers a novel protective effect of the ApoE3Ch variant against tau pathology, thus proposing new insights into Alzheimer's disease mechanisms and potential therapeutic targets

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Authors
Perez‐Corredor, P., Arevalo‐Alquichire, S., Mazzarino, R. C., O'Hare, M., Muriel‐Torres, A. F., Vacano, G. N., Vanderleest, T. E., Miller, W. P., Pineda‐Lopez, L., Patel, S., Obar, R. A., Polat, N., Kim, L. A., Arboleda‐Velasquez, J. F., & Marino, C.
Affiliations
  • Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology Harvard Medical School Boston Massachusetts USA
  • Massachusetts Eye and Ear Infirmary (US)
  • Cognitive Technologies (United States) (US)
  • Harvard University (US)
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2025-07
Volume
21
Issue
7
Pages
e70396-e70396
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.70396
PMC
PMC12242688
OpenAlex
W4412156148
Cited by
7
References
10
Citations by year
2026: 5 · 2025: 2
FWCI
4.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (Queen's University Belfast) (publishedVersion, cc-by)
Funders
  • Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
  • Good Ventures Foundation
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
APOE3
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Protein Binding, tau Proteins, Intercellular Signaling Peptides and Proteins, Mice, Apolipoprotein E3

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