The development of prevention measures and treatment strategies for Alzheimer's disease (AD) constitutes one of the highest priorities for biomedical sciences due to the high prevalence and the lack of effective therapies for this illness. Studies in animals have shown that exogenous insulin-like growth factor 2 (IGF2) has cognitive enhancing activity and anti-amyloidogenic actions in models of AD. This proposal has been designed to test the hypothesis that amelioration of AD-like pathology produced by choline supplementation in AD-model mice may be mediated by the long-term persistent induction of IGF2. We will determine if brain-derived IGF2 provides the cognitive enhancing, pro-neurogenic and anti-amyloidogenic environment in the brain using an inducible, conditional Igf2 gene deletion transgenic mouse. Choline is an essential nutrient necessary for the growth and functioning of mammalian cells. In rodents, supplementation of the maternal diet with choline during the second half of pregnancy has been shown to improve memory and cause biochemical, structural, and electrophysiological changes in brain in the offspring. In addition, perinatal choline supplementation has been shown to reduce the severity of behavioral deficits in animals prenatally exposed to alcohol, to prevent the memory impairments following seizures, to improve motor defects in a mouse model of Rett syndrome, and to alleviate anxiety and social behavioral deficits in a mouse model of autism. Using the APPswe/PS1dE9 (APP.PS1) mouse model of Alzheimer's disease (AD), we found that supplementation of dietary choline during the perinatal period dramatically reduced hippocampal amyloidosis, increased hippocampal neurogenesis, and prevented cholinergic deficits which were seen in APP.PS1 mice receiving a standard amount of choline. In addition, choline supplementation increased brain expression of IGF2 and prevented a decrease in IGF2 expression in APP.PS1 mice. We previously reported that intracerebroventricular IGF2 infusion ameliorates amyloidosis and cholinergic defects, as well as increases hippocampal neurogenesis, in the APP.PS1 mice. Together these data suggest that enhanced endogenous IGF2 production may slow down AD pathology and that some of the actions of increased choline availability during early development on the brain are mediated by IGF2. Although dietary choline availability during early life has been shown to be critical for normal brain development and to protect the brain against various insults, the 2007 National Health and Nutrition Examination Survey found that fewer than 15% of pregnant women consume the recommended amount of choline. This study will provide information on the mechanism of action of choline as modulator of AD-like pathology in a mouse model by focusing on IGF2 and, if successful, will provide mechanistic evidence in support of public health initiatives designed to promote choline nutrition to improve cognitive development and aging, and prevent AD. !
High intake of the essential nutrient, choline, during early life increases brain expression of a growth factor, IGF2, and protects Alzheimer's disease model mice from several features of AD-like pathology. The goal of this study is to understand how IGF2 mediates the beneficial effects of perinatal choline supplementation. The study will contribute to our understanding of the role of dietary choline in health promotion and disease prevention.
