ApoE3 Christchurch Clings Tightly to Tau, Averting Tangles

The quest continues to solve the curious case of a Colombian woman who dodged AD until much later in life than expected. Aliria Rosa Piedrahita de Villegas carried the Paisa presenilin-1 mutation and yet stayed free of dementia well into her 70s. Her secret? Two copies of a rare mutation in apolipoprotein E3, known as the Christchurch variant. Previous research showed ApoE3Ch barely binds lipoprotein receptors and heparan sulfate proteoglycans, which help spread toxic forms of tau pathology. In the January 15 Neuron, researchers led by Seong Kang at Emory University, Atlanta, and Keqiang Ye at Shenzhen Institutes of Advanced Technology, China, report that ApoE3Ch also binds tau directly in cells. This shields the microtubule-binding protein from an endopeptidase that otherwise generates fragments that can spread between cells.

  • ApoE3Ch binds more strongly to tau than does ApoE3.
  • This shields tau from proteolysis, preventing fragments from entering neurons and microglia.
  • Less tau uptake reduced neurotoxicity and cell death in mice.

Joseph Arboleda-Velasquez of Harvard Medical School praised the results. “Ye’s group has now provided compelling evidence showing increased binding affinity of ApoE3 Christchurch for tau and its ability to reduce tau pathology propagation and neurotoxicity in vitro and in vivo,” he wrote to Alzforum (comment below).

Kang and Ye had previously reported that ApoE3 gloms onto tau and stops it from getting chopped at asparagine 368 by asparagine endopeptidase (AEP). In contrast, ApoE4 did not bind tau, leaving it at the mercy of AEP and leading to tau pathology in mice (Kang et al., 2022). So, could ApoE3Ch, a serine-to-arginine substitution at amino acid 136 in the mature protein, offer the same protection?

Better Binder. Surface plasmon resonance (left) determined that ApoE3 R136S (Christchurch) has higher affinity (bar chart) for tau than does ApoE3. In SH-SY5Y neuroblastoma cells (right), GST-tagged tau bound more tightly to GFP-tagged ApoE3Ch than GFP-ApoE3. [Courtesy of Chen et al., 2025 Neuron.]

To find out, the scientists turned to surface plasmon resonance, a technique that quantifies molecular interactions in real time. It showed that ApoE3Ch clings onto tau monomers immobilized on sensor chips approximately eight times more tightly than does wild-type ApoE3. Similarly, in neuroblastoma cells, glutathione S-transferase-labelled tau and GFP-tagged ApoE3Ch bound tightly (image at right).

What’s the upshot of this binding? ApoE3Ch fended off tau fragmentation by AEP to a greater extent than did ApoE3.

“This was surprising,” Ye told Alzforum. “If we can prevent tau fragmentation by AEP, then tau pathology or propagation will be substantially diminished,” he predicted. Indeed, first authors Guiqin Chen, Mengmeng Wang, and colleagues found that 5xFAD mice injected with preformed tau fibrils better navigated and escaped a water maze if they were co-injected with adeno-associated virus expressing ApoE3Ch. As with the 5xFAD mice, P301S mice that express mutant human tau had a longer “freezing” time during a fear conditioning test if injected with AAV-ApoE3Ch, suggesting better cognition.

The authors argue that tight binding between ApoE3Ch and tau that prevents fragmentation, plus weak binding between ApoE3Ch and lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans, as reported previously, together prevent ApoE3Ch-bound tau from getting into neurons or microglia, stopping the spread of tau toxicity (Lalazar et al., 1988; Nov 2019 news).

Not everyone agrees. Kenneth Kosik, University of California, Santa Barbara, was unconvinced that ApoE3Ch ushers less tau into cells than does ApoE3. In a recent preprint, Kosik reported that ApoE3Ch astrocytes take up and clear more tau oligomers than does ApoE3, and that it does so by shunting tau to astrocyte lysosomes for degradation (Tian et al., 2025). Previously, scientists at David Holtzman’s lab at Washington University School of Medicine in St. Louis also showed that ApoE3Ch binds less strongly to HSPG and LRP1, but that this promotes phagocytosis and degradation of tau-preformed fibrils by myeloid cells (Chen et al., 2024).

Kang addressed some of these concerns. He noted that in vitro, there is a baseline difference between cells with ApoE3Ch and those expressing ApoE3, the former taking up much less tau. Even when the LRP1 pathway is blocked, ApoE3Ch cells still take in less tau (comment below).

Others thought that while surface plasmon resonance is highly quantitative, it may not reflect normal physiology. They pointed out that ApoE is quite abundant in the extracellular space, but because tau is sparse there, the two may not interact.

ApoE3Ch Curbs Tau Toxicity. In neurons (blue bottom), ApoE3Ch binds tightly to tau and prevents its fragmentation. In the extracellular space it prevents tau uptake into neurons and microglia. [Courtesy of Chen et al., Neuron.]

To Arboleda-Velasquez’s mind, the findings have far-reaching implications for therapeutic development. “It is now evident that [ApoE3Ch] homozygosity may not be required for protection, raising the exciting possibility that the three decades of protection observed in the homozygous [carrier] case could be achieved therapeutically in others,” he wrote.

Ye is exploring possibilities. “If we can stably express this Christchurch mutation, we can imagine using use cell transplantation therapy to substantially slow down tau spreading even for patients in the earliest stage of the disease,” he said.—Kristel Tjandra

Kristel Tjandra is a freelance writer in Springfield, Virginia.

Comments

  1. We appreciate the feedback on our work and would like to address some of the concerns. We acknowledge that the Biacore surface plasmon resonance experiment was conducted under controlled in vitro conditions, which may not fully reflect physiological environments. However, our primary goal was to observe the direct interaction between ApoE and tau, despite this limitation, and to compare ApoE3 and ApoE3Ch in tau binding. We did not specifically consider cerebrospinal fluid conditions because ApoE concentrations in the CSF are significantly lower than in the brain, and the critical interactions between these proteins in pathological progression occur within the parenchyma. Ideally, in vivo representation would involve using brain lysates, but technical challenges make it difficult to analyze interactions within such complex mixtures.

    Nevertheless, our in vitro results provide valuable evidence of a direct interaction between ApoE and tau. Furthermore, we validated this interaction in cell lysates using immunoprecipitation, which, while not an exact in vivo representation, further supports our findings.

    As to the point that ApoE3Ch increases tau uptake and clearance, the differences in our findings can likely be attributed to variations in experimental conditions, particularly differences in cell types and mouse models used across studies. We primarily used neurons and, to a lesser extent, the HMC3 microglial cell line to examine cell-to-cell spreading of tau. In contrast, Chen et al. used bone marrow-derived macrophages, which are highly phagocytic cells, to assess tau clearance through phagocytosis, while Tian et al. used astrocytes for a similar reason (Chen et al., 2024; Tian et al., 2025). Since tau receptors such as LRP1 and HSPG vary significantly in expression levels across different cell types, the mechanisms underlying neuronal tau uptake and macrophage-mediated phagocytosis may be fundamentally different.

    Despite these variations, both studies reached a common conclusion regarding ApoE3Ch's role in tau binding, which is that ApoE3Ch reduces tau binding to LRP1 through competitive inhibition. However, while they did not observe differences in tau propagation in their mouse models, our study found a reduction in tau spreading. This discrepancy may be due to differences in the mouse models used. The Cell study employed ApoE knock-in mice without amyloidosis, whereas we used 5xFAD mice, which exhibit significant Aβ pathology, to assess tau propagation in an AD-relevant context.

    References:

    Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.

    Tian X, Rivera EK, Nikitina AA, Hwang I, Smith JA, Cho YJ, Sala-Jarque J, DeBose A, Andriola C, Gollan-Meyer T, Kosik KS. Protective mechanisms against Alzheimer's Disease in APOE3-Christchurch homozygous astrocytes. 2025 Jan 21 10.1101/2025.01.21.634115 (version 1) bioRxiv.

    View all comments by Seong Kang

  2. It’s incredibly exciting to read this novel work from Keqiang Ye's lab. Our research, conducted in collaboration with Claudia Marino, now assistant professor at the University of Texas Medical Branch, used complementary approaches to identify interactors of ApoE Christchurch using proteomics, including MAPT and other key players. That work is currently under peer review.

    The convergence of Ye's findings with ours strongly suggests reproducibility and underscores the relevance of these mechanisms to the protective effects of ApoE Christchurch. From a practical standpoint, it is important to note that ApoE Christchurch’s protective effects are remarkably robust, likely driven by pleiotropic mechanisms that we are only beginning to unravel. Thus far, we have identified loss-of-function mechanisms—specifically, diminished binding to heparan sulfate proteoglycans (Arboleda-Velasquez et al., 2019)—as a critical mediator of protection, a finding now reproduced by multiple groups. This mechanism is also supported by the recessive effects observed in the extraordinary homozygous case of ApoE3 Christchurch with PSEN1 E280A, which demonstrated profound protection.

    More recently, we have begun exploring the dominant protective effects of ApoE Christchurch, including its role as a direct enhancer of Wnt signaling (Perez-Corredor et al., 2024). Ye’s group has now provided compelling evidence showing increased binding affinity of ApoE3 Christchurch for tau and its ability to reduce tau pathology propagation and neurotoxicity in vitro and in vivo. As the authors noted, this is consistent with our recent report highlighting the protection observed in heterozygous carriers (Quiroz et al., 2024). Phenotypic changes in heterozygosity align with the dominant protective effects demonstrated in Ye’s elegant work.

    From a therapeutic perspective, the implications of this work are transformative. It is now evident that homozygosity may not be required for protection, raising the possibility that the three decades of protection observed in the homozygous case could be achieved therapeutically in others. This might be accomplished by combining HSPG-binding blockers—such as the 7C11 antibody we previously characterized which does not bind ApoE Christchurch—with direct administration of ApoE3 Christchurch (Marino et al., 2024). This combination therapy holds significant potential to harness the remarkable protective effects of ApoE3 Christchurch.

    Finally, let us remember where this journey began—with Aliria Rosa Piedrahita de Villegas, the original ApoE Christchurch case, and Francisco Lopera, the legendary neurologist who treated her (Lopera 2024; Sep 2024 obituary). Their story laid the foundation for what is shaping up to be a potentially paradigm-shifting advance in Alzheimer’s disease research.

    View all comments by Joseph Arboleda-Velasquez

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References

Mutations Citations

  1. PSEN1 E280A (Paisa)
  2. APOE C130R (ApoE4)
  3. APOE R154S (Christchurch)

Research Models Citations

  1. 5xFAD (C57BL6)
  2. Tau P301S (Line PS19)

News Citations

  1. Can an ApoE Mutation Halt Alzheimer’s Disease?

Paper Citations

  1. Kang SS, Ahn EH, Liu X, Bryson M, Miller GW, Weinshenker D, Ye K. ApoE4 inhibition of VMAT2 in the locus coeruleus exacerbates Tau pathology in Alzheimer's disease. Acta Neuropathol. 2021 Jul;142(1):139-158. Epub 2021 Apr 25 PubMed.
  2. Lalazar A, Weisgraber KH, Rall SC Jr, Giladi H, Innerarity TL, Levanon AZ, Boyles JK, Amit B, Gorecki M, Mahley RW. Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J Biol Chem. 1988 Mar 15;263(8):3542-5. PubMed.
  3. Tian X, Rivera EK, Nikitina AA, Hwang I, Smith JA, Cho YJ, Sala-Jarque J, DeBose A, Andriola C, Gollan-Meyer T, Kosik KS. Protective mechanisms against Alzheimer's Disease in APOE3-Christchurch homozygous astrocytes. 2025 Jan 21 10.1101/2025.01.21.634115 (version 1) bioRxiv.
  4. Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Chen G, Wang M, Zhang Z, Hong DK, Ahn EH, Liu X, Kang SS, Ye K. ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease. Neuron. 2025 Jan 7; Epub 2025 Jan 7 PubMed.

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