Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by progressive decline in memory and cognitive functions. In addition, AD patients frequently show severe personality changes and various psychiatric symptoms, as well as epileptic and myoclonic seizures. Some of these functional disturbances may reflect altered membrane excitability of neuronal cells in AD patients. However, the underlying molecular mechanism is not known. Recently we and others reported that the voltage-gated sodium channel (Nav1) 22-subunit (22) undergoes proteolytic processing mediated by BACE1, ADAM10, and gamma- secretase, similar to the processing of the AD amyloid precursor protein (APP). 22 is essential for maintaining expression, trafficking, and cell surface localization of the Nav1 1-subunits, the major channel-forming subunits regulating membrane excitability in neuronal cells. Our preliminary data indicate that elevated BACE1 activity dramatically decreases sodium current densities by reducing cell surface expression of Nav1 1-subunits through the enhanced processing of 22 in both cell-based and animal model systems. Interestingly, we also found highly elevated 22 processing and altered Nav1 1-subunit levels in brains of AD patients with elevated BACE1 activity. Dysfunctions in Nav1 activity lead to psychiatric symptoms and epileptic seizures. Since BACE1 activities significantly increased in brains of AD patients, enhanced 22 processing and consequent Nav1 dysfunction may lead or contribute to psychiatric symptoms and epileptic seizures that frequently occur in the course of the disease. Based on this reasoning, we propose to test the hypothesis that elevated 22 processing by BACE1 and presenilin/gamma-secretase impairs the normal Nav1 metabolism including trafficking and surface expression of Nav1 1-subunits in brains of AD patients, contributing to AD pathology. To test this hypothesis, we propose the following Aims:
In Aim. 1, we will characterize the altered Nav1 metabolism by elevated BACE1 activity and its physiological effects on neuronal cells by using BACE1- transgenic mice, an animal model mimicking the elevated BACE1 activity in AD patients. In an attempt to explore the therapeutic application of our findings, we will test whether BACE1 and/or gamma-secretase inhibitors can restore altered Nav1 metabolism in BACE1-trangenic mice. In addition, we will test whether these inhibitors can affect normal Nav1 metabolism in wild-type mice as well.
In Aim. 2, we will study altered Nav1 metabolism in brains of AD patients by using immunohistochemical and biochemical methods. The goal of this proposal is to determine how altered 22 processing and Nav1 metabolism affect the physiology of neurons in AD, leading to dysfunction and selective degeneration observed in the course of the disease. Our study will also suggest potential therapeutic applications of BACE1 inhibitors and sodium channel modulating drugs in treating abnormal neuronal activities in AD patients.
In this proposal, we seek to elucidate the pathogenic contribution of altered voltage-gated sodium channel levels and activity to Alzheimer's disease. Our study will also suggest potential therapeutic applications of BACE1 inhibitors and sodium channel modulating drugs in treating abnormal neuronal activities in AD patients. ? ? ?
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