Grant Abstract: BMP9 as a Juvenile Protective Factor in Cognitive Aging

Grant Number: 5R01AG045031-04
PI Name: Blustajn
Project Title: BMP9 as a Juvenile Protective Factor in Cognitive Aging

Abstract: This proposal has been designed to test the mechanistic hypothesis that the long-term induction of expression of the growth and differentiating factor, BMP9 (also called GDF2), mediates the cognition enhancing and anti-amyloidogenic actions of perinatal choline supplementation. Choline is an essential nutrient that is frequently used as a dietary supplement. The Dietary Supplement Label Database lists over 3000 choline-containing products on the US market. However, multiple studies have shown that most Americans consume much less than the adequate intake (AI) value for this nutrient. For example, the 2007 National Health and Nutrition Examination Survey found that fewer than 15% of pregnant women consume the recommended AI amount of choline. We previously showed that perinatal choline supplementation prevented the memory decline normally observed in aged rats. Thus, cognitive decline is not an inevitable outcome of old age, but rather can be prevented by an increased supply of choline during sensitive periods of perinatal development. We also showed that perinatal choline supplementation generated a trophic brain microenvironment by increasing the concentrations of several growth factors, including BMP9, as compared to controls. Moreover, we found that Alzheimer’s disease model APPswe/PS1?E9 (APP.PS1) mice that lack BMP9 due to the targeted mutation of its gene (Bmp9–/– mice) are characterized by increased vulnerability to AD-like pathology, as evidenced by greater memory defects, and increased hippocampal amyloidosis, as compared to APP.PS1 mice that express BMP9 (Bmp9+/+). In contrast, perinatal choline supplementation of APP.PS1 mice protected them from hippocampal amyloidosis and from cholinergic deficits. Our aim is to determine the effects of choline supplementation during gestation and nursing on behavioral, cognitive, cellular and molecular phenotypes of wild type mice and AD model APP.PS1 mice with normal Bmp9 expression or with an inactivating mutation of the Bmp9 gene. If our hypothesis that BMP9 mediates the actions of choline on the brain is correct, only the former but not the latter should benefit from choline supplementation. The study will increase our understanding of the nutritional relevance of choline in food, and as a dietary supplement that improves health and protects against diseases such as AD.

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