Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer’s disease and epilepsy

  1. Huihong Li
  2. Zhiran Xie
  3. Yuxuan Tian
  4. Ruoyin Zhou
  5. Yaxi Yang
  6. Bingying Lin
  7. Si Chen
  8. Jie Wu
  9. Zihan Deng
  10. Jianwei Li
  11. Mingjie Chen
  12. Xueke Liu
  13. Yushan Sun
  14. Bing Huang
  15. Naili Wei
  16. Xiaoyu Ji

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Abstract

Alzheimer’s disease (AD) and epilepsy (EP) share a complex bidirectional relationship, yet the molecular mechanisms underlying their comorbidity remain insufficiently explored. To identify potential transcriptional programs across animal models and human patients with AD and EP, we conducted a comprehensive genome-wide transcriptomic analysis. Our investigation included mouse models of temporal lobe epilepsy (pilocarpine- and kainic acid-induced; n = 280), AD transgenic models (7 transgenic models expressing human tau or amyloid pathology; n = 257), and performed cross-species validation in human cohorts (EP: n = 182; AD: n = 301). We identified a highly conserved immune-related module across all models and patient cohorts. The hub consensus signatures of this module were centered around a microglial synaptic pruning pathway involving TYROBP , TREM2 , and C1Q complement components. Gene regulatory network analysis identified TYROBP as the key upstream hub signature. These signatures showed consistent up-regulation in both conditions and strong diagnostic potential. Differential expression analyses revealed their predominant expression in specific microglial subpopulations associated with complement-mediated synaptic pruning and immune activation. Neural circuit modeling further demonstrates the asymmetric sensitivity of synaptic pruning to network dynamics. Loss of inhibitory synapses has a disproportionately significant impact on neural network excitation/inhibition balance and synchronization. Our findings support microglial complement-mediated synaptic pruning as a conserved central pathway linking neurodegeneration to epileptogenesis, suggesting a promising therapeutic target for AD and EP comorbidity.

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Highlights

  • Genome-wide transcriptomic analysis across epilepsy (EP) and Alzheimer’s disease (AD) models and patients identified a conserved immune module.

  • The TYROBP-TREM2-C1Q microglial synaptic pruning pathway was identified as a central consensus signature across model and patient cohorts.

  • Consensus signatures possess potential diagnostic utility in AD and EP patients, with predominant expression in specific microglial subpopulations

  • Neural circuit modeling demonstrates the asymmetric effects of synaptic pruning, whereby loss of inhibitory synapses disproportionately disrupts the E/I balance, leading to increased network synchronization.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/15682703.

    Does the introduction explain the objective of the research presented in the preprint? Yes It described the need, importance and the reason for the study.
    Are the methods well-suited for this research? Highly appropriate The methods were well detailed
    Are the conclusions supported by the data? Somewhat supported
    Are the data presentations, including visualizations, well-suited to represent the data? Highly inappropriate or unclear There was no data presentation as visuals, etc. in the article, except it was kept in another place
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly
    Is the preprint likely to advance academic knowledge? Highly likely It is an area that, if advanced, will help in healthcare promotion.
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, but it needs to be improved Data should be presented using various visual aids. It should provide more detailed explanations to enable scholars from different fields to learn easily.
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes Results and discussion

    Competing interests

    The authors declare that they have no competing interests.

  2. Version published to 10.1101/2024.10.28.618752v12 on bioRxiv
  3. Version published to 10.1101/2024.10.28.618752v11 on bioRxiv
  4. Version published to 10.1101/2024.10.28.618752v10 on bioRxiv
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  13. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/14017981.

    Summary of Main Findings.

    This study reveals shared transcriptomic signatures between Alzheimer's disease and epilepsy, highlighting synaptic pruning as a potential molecular connection between the two disorders. Through detailed transcriptomic analysis, the researchers discovered that dysregulated genes related to synaptic pruning may play a role in the pathological processes of both diseases. This research offers new insights into the common mechanisms underlying neurodegeneration and neurological disorders, proposing synaptic pruning as a viable therapeutic target for both Alzheimer's and epilepsy. By linking these two conditions, the study paves the way for innovative dual-targeting therapeutic strategies that could alleviate symptoms or slow disease progression in patients with either or both conditions.

    Major Issues

    Causal Mechanisms Not Established: The study indicates associations between synaptic pruning and disease but lacks experimental validation to confirm causation. Additional mechanistic studies are necessary to determine whether changes in synaptic pruning are truly causal factors.

    Sample Size and Diversity: If the research was based on small or homogeneous sample populations, the findings may not be applicable to broader populations, particularly considering genetic and environmental variations among Alzheimer's and epilepsy patients.

    Limited Functional Validation: Although transcriptomic data show gene dysregulation, more functional experiments (e.g., in vivo or in vitro studies) are needed to elucidate the roles of these genes in synaptic pruning and disease pathology.

    Minor Issues

    Terminology Clarification: Simplifying complex terminology or providing a glossary could enhance accessibility for readers unfamiliar with specialized fields.

    Graphical Representations: Improved figures or diagrams depicting shared pathways between Alzheimer's and epilepsy could enhance understanding.

    Flow and Structure: Reorganizing sections to emphasize key findings before delving into detailed transcriptomic data could better guide readers through the research narrative.

    Competing interests

    The author declares that they have no competing interests.

  14. Version published to 10.1101/2024.10.28.618752v1 on bioRxiv