Naguib S, Torres ER, Lopez-Lee C, Fan L, Bhagwat M, Norman K, Lee SI, Zhu J, Ye P, Wong MY, Patel T, Mok SA, Luo W, Sinha S, Zhao M, Gong S, Gan L. APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition. bioRxiv. 2024 Apr 28; PubMed.
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Washington University School of Medicine
Washington University
In 2019, a case report (Arboleda-Velasquez et al., 2019) of a person who was homozygous for the APOE3 Christchurch (R136S) mutation caught the attention of many researchers studying APOE and AD, including our group. It might delay cognitive decline by 25 years, even in people with the autosomal-dominant Alzheimer’s disease mutation, PSEN1 E280A. The APOE3Ch homozygous carrier showed very limited tauopathy despite having massive amyloid deposition in the brain regions where this typically occurs in AD. Intrigued by this discrepancy between amyloid pathology and amyloid-induced tauopathy, we created a new humanized APOE3Ch mouse model and performed experiments on AD-tau seeding and spreading (Chen et al., 2024). We showed that APOE3Ch protects against amyloid-induced tauopathy. It appeared that the mechanism involves enhanced microglial responses toward neurotic plaque-tau aggregates. With in vitro experiments, we also demonstrated that a key molecular mechanism is the reduction of competitive receptor binding of APOE3Ch with LRP1/HSPG and consequently the enhancement of LRP1/HSPG-mediated tau uptake by myeloid cells. In addition, Nelson et al. introduced the Christchurch mutation into APOE4 (Nelson et al., 2023). In their study, they reported a decrease in both reactive microglia and astrocytes associated with protection against brain atrophy. Together, it is exciting that in different mouse models, R136S appears to protect amyloid-induced tauopathy and tau-induced neurodegeneration (in an APOE4 background), which prompts the idea to modify APOE to mimic the effect of the R136S variant as a therapeutic for AD.
One missing piece of the puzzle is a direct side-by-side comparison between APOE3 and APOE3Ch in a neurodegeneration model. Nelson et al. did not observe robust neuronal loss in their PS19 APOE3 mice compared with APOE4 mice (Nelson et al., 2023). In this new study, Naguib and Torres et al. compared PS19 APOE3Ch and PS19 APOE3 mice, showing a protection against P301S-mediated tauopathy and increased overall myelin in vivo with the APOECh variant. Interestingly, Naguib and Torres et al. observed a reduction of an IFN-I signature in microglia in the PS19 APOE3Ch mice. Furthermore, a cGAS inhibitor rescued synaptic loss in PS19 APOE3 mice restoring levels seen in thePS19 APOE3ch cohort. Consistent with the Gan lab’s previous publication on cGAS-STING-IFN pathway in tauopathy in vivo (Udeochu et al., 2023), this work further suggests that inhibitors targeting cGAS-STING pathway might be a promising pharmacological target for treating tauopathy and neurodegeneration.
However, what still eludes the field is the mechanism whereby protection of APOECh protects at the cellular level. At the biochemical level, there is no doubt that the APOE R136S variant reduces APOE receptor binding to LDLR, LRP1, and HSPG (Chen et al., 2024; Lalazar et al., 1988; Mah et al., 2023). At a cellular level, we hypothesized in our study, and showed that APOE3Ch impacts microglia responses toward amyloid and amyloid-induced tauopathy, likely due to the reduction in APOE3Ch’s receptor binding, because tau seeds and APOE lipoprotein particles compete for receptor binding. A recent study on the postmortem brain sample from the APOE3Ch homozygote carrier arrived at a similar conclusion, but focusing on LRP1 on astrocytes (Almeida et al., 2024). Nelson et al. suggested that the APOE3Ch protection rises from reduced uptake of paired helical fragments of tau in neurons. The molecular mechanism for this may be the same because the APOE variant difference was inhibited by heparin.
Gan and colleagues found that APOE3Ch microglia appeared to process aggregated tau fibrils more effectively, similar to what we observed in myeloid cells (Chen et al., 2024). While they previously showed that inhibition of the cGAS-STING-IFN pathway protects against tauopathy and tau-mediated neurodegeneration, it is not completely clear if APOE3Ch protects against neurodegeneration via the cGAS-STING-IFN pathway. First, reduction of microglial IFN signature in ApoECh mice may arise from the decreased neurodegeneration; second, while there are similarities there are also differences between cGAS-inhibitor- and APOE3Ch-driven changes in gene expression. This suggests that the same mechanism is not necessarily at play. Nonetheless, it is certainly possible that in the PS19 model APOE3Ch protects by influencing the cGAS-STING-IFN pathway.
Importantly, the protective effects of APOE3Ch in AD-related pathology has now been demonstrated in vivo by three independent research groups. It will be interesting to utilize this information to better understand the detailed mechanisms of its effects, as well as to test pharmacological therapies (Marino et al., 2024), gene therapies, or even cell therapies to investigate the translational potential of APOE3Ch-mediated protection against different aspects of AD pathology.
References:
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