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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Emory University
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 KangSchepens Eye Research Institute and Harvard Medical School
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-VelasquezMake a Comment
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