Epigenetic Regulation of Hippocampal Function and Cognition in Alzheimer's Disease
Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by memory loss and progressive cognitive decline. Notably, the incidence of seizures and other epileptiform activity is also 8- to 10-fold higher in AD compared to the general population. Recent evidence demonstrates that seizures in AD occur early in disease progression, and are likely major contributors to cognitive impairment in both patients and animal models of the disease. However, the mechanisms by which seizures induce cognitive deficits are poorly understood. To identify these mechanisms, we study the molecular and cellular alterations that occur downstream of seizures in the hippocampus of a transgenic AD mouse model that expresses human amyloid precursor protein (APP) with familial AD-linked mutations. The hippocampus may be especially vulnerable to seizure-related pathology, as hippocampus-dependent memory impairment is tightly linked to seizure severity in both AD patients and mouse models. Our recent efforts have focused on characterizing the effects of recurrent seizures on long-term epigenetic gene regulation. This emphasis on epigenetics follows our discovery that seizures robustly upregulate hippocampal expression of ΔFosB, an activity-dependent transcription factor with an unusually long in vivo half-life (~8 days). This long half-life allows ΔFosB to accumulate within neuronal nuclei following repetitive stimulation and modulate gene expression over extended periods of time via epigenetic histone modification. The accumulation of ΔFosB in hippocampal neurons following recurrent seizures suggests that this unique transcription factor plays a pivotal role in driving seizure-related changes in the hippocampus. Therefore, understanding ΔFosB’s role in the hippocampus may provide critical insight into the mechanisms that underlie cognitive decline in AD and other seizure-related disorders. As such, the work described in this dissertation centers around characterizing the diverse functions of ΔFosB in the hippocampus following upregulation by recurrent seizures. In the first section, we describe the hypothesis-driven identification of Calb1/calbindin-D28k as a key target of ΔFosB in the hippocampus, and how downregulation of this gene/protein by seizure-induced ΔFosB critically impacts hippocampal function and cognition. In the second section, we explore how ΔFosB mediates a potential trade-off between neuronal function and neuroprotection under excitotoxic conditions. In the final section, we take a broad and unbiased approach, using high-throughput sequencing of material obtained from ΔFosB chromatin immunoprecipitation (ΔFosB ChIP-seq) to simultaneously identify thousands of ΔFosB gene targets in the hippocampus. The results of ChIP-seq have provided key insight into the breadth of ΔFosB’s influence on the hippocampal network, highlighting diverse functional domains regulated by ΔFosB in this brain region.
You, Jason C, "Epigenetic Regulation of Hippocampal Function and Cognition in Alzheimer's Disease" (2017). ProQuest ETD Collection - Thomas Jefferson University. AAI10604252.