Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

APOE3ch alleviates Aβ and tau pathology and neurodegeneration in the human APPNL-G-F cerebral organoid model of Alzheimer’s disease

Cell Research (2024)Cite this article

Subjects

Dear Editor,

Research in Alzheimer’s disease (AD) has greatly benefited from the genetic studies of rare autosomal dominant mutations.1 In a recent case study of the world’s largest early onset AD pedigree with presenilin 1 (PSEN1) mutation, an individual was identified to have a high amyloid burden but low tau measurements, and an unusually delayed onset of cognitive impairment.2 Whole-exome sequencing revealed an additional rare homozygous mutation of APOE3 Christchurch (APOE3ch, R136S) as the potential protective factor for AD. APOE3 is one of variants in the Apolipoprotein E (APOE) gene, which has been extensively studied for its association with sporadic AD.3 APOE has three variants, ε2, ε3 and ε4; and APOE ε4 (APOE4) allele confers significantly increased risk for developing AD, relative to the common APOE ε3 (APOE3) allele. Exactly how different variants of APOE alter amyloid-β (Aβ) and tau pathology and neurodegeneration is an active area of research.4 While the identification of APOE3ch mutation opens a door for new investigations, the rarity of the APOE3ch makes it hard to study its underlying mechanisms in humans. Further, whether the APOE3ch mutation affects neuronal death and other AD pathophysiology such as neuroinflammation remains to be demonstrated.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: APOE3ch alleviates Aβ and tau pathology and suppresses neurodegeneration in the APPNL-G-F forebrain organoids.

References

  1. Frisoni, G. B. et al. Nat. Rev. Neurosci. 23, 53–66 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Arboleda-Velasquez, J. F. et al. Nat. Med. 25, 1680–1683 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Nat. Rev. Neurol. 15, 501–518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Martens, Y. A. et al. Neuron 110, 1304–1317 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scearce-Levie, K., Sanchez, P. E. & Lewcock, J. W. Nat. Rev. Drug Discov. 19, 447–462 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Pang, K. et al. Cell Res. 32, 157–175 (2022).

    Article  CAS  PubMed  Google Scholar 

  7. Qian, X. et al. Nat. Protoc. 13, 565–580 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhou, Y., Song, H. & Ming, G. L. Nat. Rev. Genet. 25, 26–45 (2024).

    Article  CAS  PubMed  Google Scholar 

  9. Self, W. K. & Holtzman, D. M. Nat. Med. 29, 2187–2199 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. He, Z. et al. Nat. Med. 24, 29–38 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Patani, R., Hardingham, G. E. & Liddelow, S. A. Nat. Rev. Neurol. 19, 395–409 (2023).

    Article  CAS  PubMed  Google Scholar 

  12. Yuan, J., Amin, P. & Ofengeim, D. Nat. Rev. Neurosci. 20, 19–33 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Eichmuller, O. L. & Knoblich, J. A. Nat. Rev. Neurol. 18, 661–680 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen, Y. et al. Cell 187, 428–445.e20 (2024).

    Article  CAS  PubMed  Google Scholar 

  15. Nelson, M. R. et al. Nat. Neurosci. 26, 2104–2121 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (2017YFE0126500), the National Natural Science Foundation of China (31730034, U22A20299), Beijing Advanced Innovation Center for Human Brain Protection, Beijing Academy of Artificial Intelligence (BAAI,  20222001736) to B.L., and the National Natural Science Foundation of China (82071207), Beijing Municipal Natural Science Foundation (7232099) to F.M.

Author information

Author notes

  1. These authors contributed equally: Hang Liu, Fan Mei.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, China

    Hang Liu, Rongrong Ye, Xinyu Han, Shudan Wang, Yan Ding, Yun Zhi, Keliang Pang, Wei Guo & Bai Lu

  2. Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    Fan Mei

  3. 4B Technologies, Limited, Shanghai, China

    Rongrong Ye & Xinyu Han

  4. Beijing Academy of Artificial Intelligence, Beijing, China

    Bai Lu

  5. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China

    Bai Lu

Authors
  1. Hang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fan Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rongrong Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinyu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shudan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yun Zhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Keliang Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bai Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.L., H.L. and F.M. conceived the study and designed the major experiments. H.L., F.M., R.Y., X.H., S.W., Y.D., Y.Z., K.P. and W.G. performed the experiments and analyzed the data. The manuscript was written by B.L. and F.M. with input from all of the authors.

Corresponding authors

Correspondence to Fan Mei or Bai Lu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, H., Mei, F., Ye, R. et al. APOE3ch alleviates Aβ and tau pathology and neurodegeneration in the human APPNL-G-F cerebral organoid model of Alzheimer’s disease. Cell Res (2024). https://doi.org/10.1038/s41422-024-00957-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41422-024-00957-w

Search

Advanced search

Quick links