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April 15th, 2025
Version: 10
Shantou University Medical College
systems biology
biorxiv

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

Li, H.Open in Google Scholar•Xie, Z.Open in Google Scholar•Tian, Y.Open in Google Scholar•Yang, Y.Open in Google Scholar•Lin, B.Open in Google Scholar•Chen, S.Open in Google Scholar•Li, J.Open in Google Scholar•Wu, J.Open in Google Scholar•Chen, M.Open in Google Scholar•Liu, X.Open in Google Scholaret al.

Alzheimers 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 regulator with the highest total connectivity. 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.

Graphic abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/618752v8_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@1062616org.highwire.dtl.DTLVardef@ae6fe7org.highwire.dtl.DTLVardef@34ab24org.highwire.dtl.DTLVardef@1d00416_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGenome wide transcriptomic analysis across epilepsy (EP) and Alzheimers disease (AD) models and patients identified a conserved immune module. C_LIO_LITYROBP-TREM2-C1Q microglial synaptic pruning pathway was identified as central consensus signature across model and patient datasets. C_LIO_LIConsensus transcriptional signatures showed strong diagnostic value in both AD and EP patient cohorts. C_LIO_LIComputational modeling demonstrated asymmetric impact of synaptic pruning, with inhibitory synapse loss disproportionately disrupting E/I balance, thereby driving hyperexcitability and increased network synchronization. C_LI

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