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<p>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; <i>n</i> = 280), AD transgenic models (7 transgenic models expressing human tau or amyloid pathology; <i>n</i> = 257), and performed cross-species validation in human cohorts (EP: <i>n</i> = 182; AD: <i>n</i> = 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 <i>TYROBP</i>, <i>TREM2</i>, and <i>C1Q</i> complement components. Gene regulatory network analysis identified <i>TYROBP</i> as the key regulatory signature. These signatures showed consistent up-regulation in both conditions and 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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年10月26日

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  • Huihong Li,
  • Zhiran Xie,
  • Yuxuan Tian,
  • Ruoyin Zhou,
  • Yaxi Yang,
  • Bingying Lin,
  • Si Chen,
  • Jie Wu,
  • Zihan Deng,
  • Jianwei Li,
  • Mingjie Chen,
  • Xueke Liu,
  • Yushan Sun,
  • Naili Wei,
  • Bing Huang,
  • Xiaoyu Ji

摘要

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 regulatory signature. These signatures showed consistent up-regulation in both conditions and 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.