Shared Transcriptomic Signatures Reveal Synaptic Pruning as a Link Between Alzheimer’s Disease and Epilepsy

This article has been Reviewed by the following groups

Read the full article See related articles

Abstract

Alzheimer’s disease (AD) and epilepsy (EP) exhibit a complex, bidirectional relationship, however, the molecular mechanisms underlying their comorbidity remain poorly understood. To address this gap, we analyzed large-scale transcriptomic datasets from pilocarpine-induced EP mouse models (n = 200), two AD mouse models expressing human tau (rTg4510) or amyloid precursor protein (J20) (n = 141), and transcriptomic profiles from AD and EP patient cohorts. Differential expression and weighted gene co-expression network analyses identified a highly conserved immune-related module enriched in microglia-specific genes, particularly Tyrobp , Trem2 , and C1q complement component genes ( C1qa , C1qb , C1qc ) implicated in the synaptic pruning pathway. Gene regulatory network analysis showed that Tyrobp regulates these C1q components gene through Trem2 . These hub genes were markedly upregulated in both models and human patient datasets, preserved their regulatory relationship across species, and displayed strong diagnostic value. Cell composition deconvolution and single-cell transcriptomics confirmed their high, cell-type-specific expression in microglia from both animal model and human patient datasets. Moreover, computational modeling indicated that excessive synaptic pruning, particularly of inhibitory synapses, alters the excitation/inhibition (E/I) balance toward excitability that increases neural network synchrony. Collectively, our findings reveal how microglial complement-driven synapse elimination may promote both seizure activity and cognitive decline. We suggest that microglia play a central role in the comorbidity of EP and AD, and further exploration of this synaptic pruning pathway in the context of EP may provide promising insights into the treatment of AD and EP comorbidity.

Graphic abstract

Highlights

  • Transcriptomic analysis across epilepsy (EP) and Alzheimer’s disease (AD) models and patient datasets revealed a conserved immune gene module.

  • Shared transcriptomic signatures identified in animal models show strong diagnostic value in both AD and EP patient datasets.

  • Tyrobp-Trem2-C1q microglial synaptic pruning pathway was identified as a central shared molecular mechanism across model and patient datasets.

  • Computational modeling revealed that excessive synaptic pruning, particularly of inhibitory synapses, alters E/I balance toward excitability and increases synchrony in neural network.

Article activity feed

  1. 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.