Shared Transcriptomic Signatures Reveal Synaptic Pruning as a Link Between Alzheimer’s Disease and Epilepsy
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Abstract
The mechanism of epileptogenesis in Alzheimer’s disease (AD) remains poorly understood, though growing evidence indicates shared molecular mechanisms between epilepsy (EP) and AD. This study aims to reveal these overlapping molecular mechanisms by reanalyzing two extensive bulk RNA-seq datasets: one from a pilocarpine-induced temporal lobe epilepsy (TLE) model (n=200) and the other from AD models, specifically rTg4510 (TG) tauopathy and J20 amyloidosis (n=141). We identified 101 differentially expressed genes (DEGs) shared between EP and the tauopathy model, though none were shared between EP and the amyloidosis model. These shared DEGs were significantly enriched in immune-related terms. Weighted gene co-expression network analysis (WGCNA) revealed a highly preserved immune module strongly associated with both EP and tauopathy models, which also significantly overlapped with modules constructed from EP and AD human patient datasets. This module contained 19 shared hub genes enriched in the synapse pruning biological process, with shared regulatory network analysis revealing a pathway where Tyrobp regulates C1q component genes through Trem2. Cell composition deconvolution showed decreased neuronal and increased microglial composition in both EP and tauopathy models, with strong correlations observed between these cellular composition changes and the expression of shared hub genes. Further validation using single-cell/nucleus sequencing data from EP and AD patients confirmed a high microglia-specific expression of key genes, including Tyrobp, Trem2, and C1q components, in both EP and AD patients relative to other hub genes. These findings suggest that immune-related processes, particularly microglial-mediated synaptic pruning, are essential in both disorders and may drive neurodegeneration and epileptogenesis.
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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 …
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.
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