Alzheimer's disease (AD) is a neurodegenerative disease that accounts for approximately 50-80% of dementia cases worldwide. The disease is characterized by progressive cognitive decline and severe memory loss. As current therapies for AD offer limited benefit if any, the need to better understand the mechanisms of cognitive decline in AD cannot be overstated. The key finding that AD is associated with seizures may provide valuable insight into these mechanisms. Recent evidence suggests that seizures in AD are not just incidental, but may play an active role in contributing to cognitive decline early in disease progression. Consistent with this, treatment of both AD patients and AD mouse models with antiepileptics improves cognitive function. Therefore, understanding how seizures contribute to cognitive decline may open an avenue to discover novel therapies that can mitigate cognitive deficits and improve quality of life for AD patients, as well as for patients wih other neurological disorders accompanied by seizures. As such, this proposal focuses on the molecular and cellular changes induced by seizures in the hippocampus, a brain region severely affected by AD. Preliminary studies utilizing transgenic mice that express the human amyloid precursor protein (APP) carrying disease-linked mutations revealed that these mice exhibited epileptic spike activity and seizures as early as two months of age, just prior to the onset of cognitive deficits and significantly earlier than amyloid plaque deposition. Furthermore, examination of hippocampi in these mice showed markedly increased expression of a transcription factor ?FosB. This finding was particularly interesting considering that the increas in ?FosB expression corresponded with both epileptic activity in the brain as well as cognitive impairment. Previous studies of ?FosB in other brain regions demonstrated that this transcription factor has an unusually long half-life (on the order of weeks) and interacts with HDACs. As such, ?FosB may play an important role in long-term epigenetic gene regulation. Notably, our preliminary investigation of ?FosB in the hippocampus revealed two important gene targets: cFos and calbindin-D28k. Since these genes play important functions in synaptic plasticity as well as cell survival, their regulation by ?FosB supports the hypothesis that ?FosB contributes to both neuroprotection and synaptic dysfunction during states of chronic neuronal hyperexcitation. Therefore, the goals of this proposal are to elucidate the functions of ?FosB in AD and other seizure-related disorders.
The Aims of this proposal are to 1) evaluate whether expression of ?FosB is sufficient to drive gene expression changes and cognitive dysfunction in vivo and 2) investigate the mechanisms by which ?FosB epigenetically regulates target genes, and the role that ?FosB plays in neuroprotection in vitro. Results from these studies will pave the way for the development of much-needed novel therapies to improve cognitive function in AD and other seizure-related disorders.

Public Health Relevance

Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive cognitive decline and an increased incidence of seizures. Recent studies suggest that seizures actively contribute to cognitive decline, but how they do so is unclear. Understanding the molecular mechanisms by which seizures affect cognition and brain function will pave the way for novel therapeutics for AD as well as other neurological disorders accompanied by seizures.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F03A-N (20)L)
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Mackiewicz, Miroslaw
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Thomas Jefferson University
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United States
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You, Jason C; Stephens, Gabriel S; Fu, Chia-Hsuan et al. (2018) Genome-wide profiling reveals functional diversification of ?FosB gene targets in the hippocampus of an Alzheimer's disease mouse model. PLoS One 13:e0192508
Corbett, Brian F; You, Jason C; Zhang, Xiaohong et al. (2017) ?FosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease. Cell Rep 20:344-355
You, Jason C; Muralidharan, Kavitha; Park, Jin W et al. (2017) Epigenetic suppression of hippocampal calbindin-D28k by ?FosB drives seizure-related cognitive deficits. Nat Med 23:1377-1383