The effects of BMP9 and perinatal choline supplementation on the APP.PS1 mouse model of Alzheimer's disease
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Abstract
Alzheimer’s disease (AD), a highly prevalent neurodegenerative illness, represents a major challenge to biomedical science due to the current lack of effective therapies. Preventative strategies are often overlooked although they have the potential to be highly beneficial. Nutrition is a critical aspect of health and prenatal nutrition has the potential to impact one’s health throughout life. Choline is an essential nutrient that although present in many foods, is often under-consumed in the United States. Several studies find that only 15% of pregnant mothers meet the adequate daily intake of choline. Prenatal choline has been associated with enhanced cognitive performance of offspring in both rodents and humans. Previous studies have shown that high perinatal intake of choline ameliorates AD-related pathology features in the APP.PS1 mouse model of this disease. In this study, perinatal diets containing supplemental and standard levels of choline were given to APP.PS1 and WT mice. Additionally, to investigate the effects of bone morphogenic protein 9, (BMP9) mice either had two (Bmp9+/+) or no copies of the gene (Bmp9-/-). BMP9 is a secreted protein that facilitates the acquisition of the cholinergic phenotype of basal forebrain cholinergic neurons (BFCNs). BFCNs are particularly vulnerable to the pathophysiologic process of AD. Because of this, BMP9 may represent a mechanism by which perinatal choline supplementation acts to ameliorate pathologic features of AD. Behavioral tests were conducted to evaluate motor activity, anxiety, and cognition longitudinally at 6 and 9 months of age. APP.PS1 mice given control-diet displayed significantly lower anxiety-like behaviors and greater locomotor activity than their counterparts given choline supplementation during development. Additionally, mice with Bmp9 gene inactivations exhibited fewer anxiety-like behaviors and greater locomotor activity than Bmp9+/+ mice. In the Barnes maze test of visuo-spatial learning and memory, APP.PS1 mice were more impaired as compared to WT mice, and this impairment was reduced in APP.PS1/Bmp9+/+ mice that had received perinatal choline supplementation. Bmp9-/- mice also exhibited impairments in escape behavior in the Barnes maze and this behavior was largely unaffected by perinatal choline. Coronal brain sections were stained with a β-amyloid antibody and hippocampal and cortical regions were analyzed for amyloid plaque content. Amyloid plaque counts increased with perinatal choline supplementation in the hippocampus, in contrast with previous works. Additionally, males with Bmp9 gene inactivations had lower plaque levels in the hippocampus than the Bmp9-/- males. These data do not directly align with behavioral data or previous reports that perinatal choline supplementation ameliorates amyloidosis in AD mouse models. Despite the contradictory amyloid plaque data, perinatal choline supplementation ameliorates spatial learning and memory impairment in APP.PS1 mice in this study. This is consistent with previous reports and supports previous literature indicating the life-long beneficial effects of supplemental choline during development on cognitive function. In the context of AD, dietary factors that affect cognitive function could represent a valuable preventative strategy. This study provides insight into the effects of Bmp9 gene inactivations in the context of AD and perinatal diet containing supplemental choline.