Neurogenic effects of amyloid beta-proteins & gangliosides in Alzheimer's Disease

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DESCRIPTION (provided by applicant): In the past decade, major progress has been made in recognizing the biological potential of neural stem cells in neurogenesis and neural repair. This progress has generated tremendous interest in utilizing these multipotent cells for the treatment of a variety of neurodegenerative disorders. There is an awareness that neurogenesis can occur in the adult brain that may play important roles not only in learning and memory, but also in the functional recovery from brain injuries. In particular, there is a growing body of literature documenting the presence of neurogenesis in the brain of Alzeheimer's disease (AD). This latter observation suggests that abnormalities in neural stem cells and/or neural progenitor cells (NSCs/NPCs) may contribute to the pathogenesis of neurodegenerative diseases, such as AD. Thus, characterization of neurogenesis during disease development should provide possibilities for the treatment of AD and related disorders. Since amyloid B-proteins (ABs) and amyloid B-protein precursor (APP) have been shown to interact with gangliosides that are known to affect neuronal survival and differentiation, such interaction should assume particular importance. Our working hypothesis is that ABs and APP could impair the neurogenic potential of NSCs/NPCs, which contributes to the pathogenesis of AD. Since gangliosides are expressed in senile plaques in AD and appear to interact with ABs and APP, they can potentially be exploited as therapeutic agents for the treatment of AD. To test these hypotheses, we propose the following specific aims to examine the proliferation and survival of NSCs/NPCs in AD. (1). We will examine the effects of ABs and APP on the fate (survival, proliferation and differentiation) of cultured NSCs/NPCs prepared from embryonic brains. (2). We will examine changes in ganglioside composition during neurogenesis, especially in caveolae where signaling events occur. (3). We will examine the effect of gangliosides on ABs and APP on the fate of NSCs/NPCs in vitro. As a short-term goal, we wish to clarify the role of ABs and ABs/ganglioside complexes on NECs that may underlie the pathogenic mechanisms of AD. Our long-term goal is to develop a ganglioside therapy for enhancing neurogenesis in AD.