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

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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 consensus transcriptional programs across animal models and human patients with AD and EP, we conducted comprehensive genome-wide transcriptomic analyses of multiple datasets. Our investigation included mouse models of temporal lobe epilepsy (pilocarpine- and kainic acid-induced; n = 280), mouse models of AD (7 transgenic models expressing human tau or amyloid pathology; n = 257), and performed cross-species validation in human cohorts (EP: n = 176; AD: n = 253). Our unsupervised gene co-expression analysis revealed 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 hub consensus signatures showed consistent upregulation in both human AD and EP cohorts, preserved their regulatory relationship across species, and demonstrated strong diagnostic value. Computational modeling further demonstrated asymmetric sensitivity of synaptic pruning on neural network dynamics, with inhibitory synapse loss exerting disproportionately larger effects on excitation/inhibition (E/I) balance shifting it toward hyperexcitability and increasing neural network synchrony. Our findings indicated microglial complement-mediated synaptic pruning as a conserved central pathway linking neurodegeneration to epileptogenesis and suggested that targeting this pathway may offer therapeutic benefits 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.

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

  • Consensus transcriptional signatures showed strong diagnostic value in both AD and EP patient cohorts.

  • Computational modeling demonstrated asymmetric impact of synaptic pruning, with inhibitory synapse loss disproportionately disrupting E/I balance, thereby driving hyperexcitability and increased network synchronization.

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    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.