Rationale:
Alzheimer’s Disease (AD) is characterized by cognitive decline, amyloid plaques, and neurofibrillary tangles. AD is also associated with increased incidence of epileptiform activity and seizures. However, not all individuals with AD exhibit seizures, but those that do experience faster cognitive decline. Therefore, understanding the mechanisms that underlie resilience or susceptibility to development of epilepsy in AD could lead to novel therapies to prevent epilepsy in AD and improve cognitive outcomes.
Transgenic mouse models of AD neuropathology also exhibit differential susceptibility to development of epilepsy. We studied mice that express mutant human amyloid precursor protein (APP, Line J20). While all APP mice display similar epileptiform spikes and seizure activity at early ages, a distinct phenotypic divergence occurs at later ages. This divergence is driven by a subset of “resilient” mice that stop exhibiting epileptiform activity and seizures, and exhibit normal spatial memory, whereas the remaining mice are “susceptible” and continue exhibiting epileptiform activity and impaired spatial memory. Investigating the mechanisms that drive phenotypic divergence could reveal novel therapeutic strategies to control or prevent epilepsy in AD.
Methods:
We used hippocampal expression of ΔFosB as a proxy for seizure activity in APP mice. ΔFosB is an activity-dependent transcription factor that accumulates in chronically active neurons, which we previously published is a reliable marker of seizure history in APP mice. This enabled us to categorize APP mice as resilient (low ΔFosB) or susceptible (high ΔFosB) to hyperexcitability. We also characterized spatial memory. We performed RNA-sequencing of the dentate gyrus in resilient and susceptible APP mice, and in nontransgenic (NTG) controls. Differential gene expression and gene ontology analyses highlighted genetic pathways exclusively differentially regulated in resilient or susceptible APP mice.
Results:
Susceptible APP mice with high ΔFosB exhibited the highest number of differentially expressed genes (DEGs) relative to NTG controls, and these DEGs were enriched in pathways related to neuronal activity, cellular stress, and inflammation. Resilient APP mice with low ΔFosB exhibited much fewer DEGs relative to NTG controls. Some pathways implicated in resilience include oxytocin signaling and other genes that support interneuron activity.
Conclusions:
Like patients with AD, individual APP mice have differential susceptibility to developing epilepsy. Resilient APP mice have reduced epileptiform activity and intact spatial memory whereas susceptible APP mice continue to exhibit epileptiform activity and impaired spatial memory. RNA-sequencing of the dentate gyrus revealed pathways specifically altered in either epilepsy-susceptible or epilepsy-resilient APP mice. These results provide a rich dataset for probing the pathways that influence resilience versus susceptibility to seizures in AD.
Funding:
Supported by NIH grants AG085919 (CS), NS085171 and NS086965 (JC), and the Belfer Neurodegeneration Consortium at MDACC.