Network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease.

摘要

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline and severe impairments of memory, especially memory dependent on the hippocampus. It is becoming increasingly clear that network dysfunction, manifested as seizures and epileptiform activity, is not only prevalent in the hippocampus and other brain regions of AD patients and mouse models, but that it directly contributes to hippocampus-dependent cognitive deficits. However, the precise mechanisms governing how this epileptiform activity arises, develops, and contributes to cognitive deficits in AD remains unknown. This dissertation addresses these questions by studying molecular, physiological, and behavioral abnormalities in a well-characterized mouse model of AD (henceforth referred to as APP mice).;One alteration observed in AD that is hypothesized to contribute to the generation of network dysfunction is reduced expression of functional Nav1.1&agr;, a voltage-gated sodium channel. Nav1.1&agr; has been shown to be critical for suppressing epileptiform activity in nontransgenic (NTG) and APP mice. However, the underlying mechanism of reduced Nav1.1&agr; expression in APP mice remains unclear. We were able to provide data supporting a model in which beta secretase 1 (BACE), an enzyme whose expression in increased in AD, promotes the cleavage of Navbeta2, an auxiliary subunit for Nav1.1&agr;. We hypothesize that this mechanism results in decreased expression of functional Nav1.1&agr; and provides a possible mechanism whereby network dysfunction arises in AD.;Electroencephalography indicates a wide range of network dysfunction in AD patients and mouse models, including non-convulsive seizures that are dependent on the corticothalamic network. Corticothalamic network dysfunction is consistent with behavioral alterations experienced by AD patients including deficits in sleep maintenance, attention, and cognitive processing. Despite this, the precise nature of corticothalamic network dysfunction in AD remains unclear. Using immunohistochemistry and electrophysiology, we were able to identify key components of the corticothalamic network that are dysfunctional in APP mice. Importantly, our proposed model of corticothalamic network dysfunction is consistent with behavioral deficits observed in AD patients and mouse models and provides evidence suggesting that corticothalamic network dysfunction may directly contribute to hippocampus dysfunction.;Recently it has been shown that hippocampus dysfunction directly contributes to AD-related hippocampus deficits in patients and mouse models. However, it is unknown how network dysfunction can contribute to cognitive deficits even during seizure-free periods. We showed that seizures drive increases in DeltaFosB, a transcription factor with an unusually long half-life. We showed that increased DeltaFosB contributes to memory deficits by epigenetically suppressing c-fos, a gene that is critical for hippocampus-dependent memory. These results provided a mechanism for seizure-induced cognitive deficits in epilepsy and AD.