Alzheimer’s disease (AD) is a neurodegenerative disease affecting 50 million people worldwide. There is increased prevalence of epilepsy in patients with AD, and the two diseases are thought to have a bi-directional association, however, the mechanism underlying this association remains unknown. This study aimed to investigate potential mechanisms of synergy between recurrent seizures and already-present amyloid pathology in a well-established model of AD.
Transgenic 5xFAD mice (N=20) and WT littermates (N=22) underwent electrical amygdala kindling to induce epilepsy phenotype or were treated as sham (no epilepsy). Kindling rate, seizure severity and cognitive behavioural performance were compared across the kindled and sham 5xFAD and WT mice. Seven days after the last induced seizure, the hippocampal tissue was harvested for RNA sequencing (ipsilateral) and immunohistochemical (contralateral) analyses.
The 5xFAD mice showed significantly impaired spatial memory (p<0.05) and increased susceptibility to kindling-induced seizures (p<0.001) compared to WT littermates. Transcriptomic profiling and differential expression analysis revealed profound overexpression of genes involved in reactive gliosis and neuroinflammatory pathways in the kindled-5xFAD group compared to sham-5xFAD and WT groups. Gene coexpression network analysis identified modules of immediate early genes (IEG) showing significant (p<0.00001) correlation with kindled-5xFAD group, but not shams. The regulatory hub genes of this module (Pcdh8, Nptx2) are activity-dependent synaptic plasticity-related genes, which are involved in synapse formation and maintenance in homeostatic conditions and lead to loss of dendritic spine density if deregulated.
Our results demonstrate a significant synergistic interaction between AD pathology and seizures, which may be mediated by activity-induced IEGs and reactive gliosis.