Friday, May 16, 2025
5/16/2025
Genetic resiliency to disease progression in Alzheimer's disease - PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is marked by impaired cognition and memory loss. AD patients also exhibit 5–10-fold increased incidence of seizure activity compared to age-matched controls, with one study finding 42% experienced subclinical epileptiform activity using extended EEG monitoring. Epileptiform activity predicts more severe cognitive decline, and treatment with antiseizure drugs slows cognitive decline. Notably, there are individuals who exhibit AD neuropathology on autopsy despite exhibiting normal cognition, referred to as non- demented with AD neuropathology (NDAN). The mechanisms by which NDAN individuals maintain intact cognition are unknown, although social interaction is associated with reduced risk of dementia in older adults. Transgenic mice overexpressing mutant human amyloid precursor protein, which causes overproduction of Aβ (APP mice, Line J20), also exhibit subclinical epileptiform and seizure activity, with a subset demonstrating “resilience” similar to NDAN individuals. Around 30% of APP mice stop having seizure activity and develop normal spatial memory by 3-4 months of age, despite having comparable levels of Aβ and seizure history to “susceptible” APP littermates, who exhibit worsening memory and continued seizure activity. To stratify mice as resilient or susceptible, we use ΔFosB expression in the dentate gyrus (DG) as a proxy, as we have previously published ΔFosB as an excellent marker of chronic hyperexcitability, with the magnitude of ΔFosB expression corresponding directly with both seizure frequency and spatial memory deficits. Resilient APP mice have ΔFosB levels similar to NTG littermates, while susceptible APP mice express significantly more ΔFosB. To investigate differences between resilient and susceptible APP mice, we examined an RNA-seq dataset generated using DG samples from resilient and susceptible APP mice and NTG littermate controls. We identified 73 genes as “resilience genes”, as differential expression was only observed in resilient mice relative to NTG and susceptible mice. Of the resilience genes identified, I further examined oxytocin receptor (Oxtr), given its high AGORA score (suggesting relevance to human AD) and oxytocin’s role in promoting social behaviors, as social isolation is a risk factor for AD. Oxytocin has also been implicated in reducing seizure activity and improving spatial memory in mouse models of epilepsy and AD, respectively. Preliminary data indicated that resilient APP mice exhibit increased oxytocin signaling to the hippocampus. Notably, chronic oxytocin treatment in APP mice reduced ΔFosB levels to near NTG levels, suggesting oxytocin may confer resilience to APP mice. To investigate the role of oxytocin in resilience to AD progression, I will 1) characterize the natural time course of changes in oxytocin signaling in resilient APP mice and investigate underlying mechanisms, and 2) determine necessity and sufficiency of oxytocin signaling in conferring resilience to AD progression. By identifying underlying genetic mechanisms conferring this natural resilience, we can target these pathways for exogenous manipulation in an effort to artificially confer resilience to AD progression.
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