The past two decades have witnessed considerable excitement in realizing the biological potential of NSCs in neurogenesis and neural repair. The tremendous amount of progress made has generated keen interest in utilizing multipotent NSCs for neural repair and for the treatment of a variety of neurodegenerative diseases. There is an awareness that neurogenesis can occur in the adult brain and that it may play important roles not only in learning and memory, but also in functional recovery from brain injuries. This latter observation also points to the fact that impairment of NSCs and/or neural precursor cells (NPCs) may contribute to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Conversely, characterization and promotion of neurogenesis during disease development should provide possibilities for the treatment of AD and related diseases. Sinceamyloid 2- proteins (A2s) and amyloid precursor protein (APP), possible causes of AD, have been shown to interact with gangliosides that are known to have neuroprotective effects, such an interaction could assume particular importance. Our working hypothesi is that A2s and APP, under certain conditions, could impair the neurogenic potential of NSCs/NPCs, and that impairment contributes to the pathogenesis of AD. Since gangliosides are expressed in senile plaques in AD and appear to interact with A2s and APP, they can potentially be exploited as therapeutic agents for the treatment of AD. To test this hypothesis, we propose the following specific aims: (1)To examine changes of ganglioside composition and neurogenesis in brains of AD model mice. (2)To examine the effects of pretreatment of gangliosides with A2s and APP on the fate of NSCs (survival, proliferation, and differentiation). As a short-term goal, we will clarify the role of A2s and A2/ganglioside complexes in NSCs that may underlie the pat hogenic mechanisms o f A D. S ince t here hav e not been any e ffective t herapies for t his neurodegenerative disorder and attempts to rescue neurons are ineffective despite the expenditure of an enormous amount of fund from pharmaceutical companies, our long-term goal is to seek strategies to promote adult neurogenesis in AD brain to achieve functional recovery.

Public Health Relevance

Brain stem cells are important not only in learning and memory but in the treatment of various brain injuries and neural repair. Gangliosides play a pivotal role modulating adult brain stem cells under normal and disease conditions such as Alzheimer's disease (AD). Our veterans are particularly predisposed to developing AD due to several precipitating factors including brain injury, mental stress, personality changes, and mood swings. Therefore, research in AD is of particular importance to our aging veterans. Our long-term goal is to seek strategies to promote ganglioside mediated adult neurogenesis in AD brain to achieve functional recovery.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cellular and Molecular Medicine (CAMM)
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Charlie Norwood VA Medical Center
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Itokazu, Yutaka; Wang, Jing; Yu, Robert K (2018) Gangliosides in Nerve Cell Specification. Prog Mol Biol Transl Sci 156:241-263
Itokazu, Yutaka; Tsai, Yi-Tzang; Yu, Robert K (2017) Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells. Glycoconj J 34:749-756
Tsai, Yi-Tzang; Itokazu, Yutaka; Yu, Robert K (2016) GM1 Ganglioside is Involved in Epigenetic Activation Loci of Neuronal Cells. Neurochem Res 41:107-15
Itokazu, Yutaka; Yu, Robert K (2014) Amyloid ?-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and notch signaling. Mol Neurobiol 50:186-96
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Itokazu, Yutaka; Kato-Negishi, Midori; Nakatani, Yoshihiko et al. (2013) Effects of amyloid ?-peptides and gangliosides on mouse neural stem cells. Neurochem Res 38:2019-27