Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer’s disease and epilepsy
- Posted
- Server
- bioRxiv
- DOI
- 10.1101/2024.10.28.618752
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 involvingTYROBP,TREM2, andC1Qcomplement components. Gene regulatory network analysis identifiedTYROBPas 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.
Graphic abstract
Highlights
Genome wide transcriptomic analysis across epilepsy (EP) and Alzheimer’s disease (AD) models and patients identified a conserved immune module.
TYROBP-TREM2-C1Qmicroglial 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.