Dietary glycomacropeptide (GMP) for neuroprotection and cognitive enhancement

描述(申请人提供)：阿尔茨海默氏病的特征是β-淀粉样蛋白(Abeta)在大脑中聚集，广泛的神经变性和认知能力下降。我们的工作集中在改善阿尔茨海默病的病理和通过改变脑神经节苷脂的分布来改善记忆。我们已经证明，在动物模型中，在体内操纵脑神经节苷脂具有神经保护作用，减少淀粉样蛋白聚集，并改善行为。尽管这两种手法不同，但它们都有提高大脑中GM1水平的能力。GM1已被证明在许多不同的制剂中具有神经保护和增强认知的作用。一份发表在野生型仔猪身上的报告表明，饮食中的糖巨肽(GMP)可以改善空间记忆，增加大脑中唾液酸神经节苷脂的水平。虽然这项研究没有报告特定神经节苷脂的水平，但增强的认知表明GM1升高。我们的目标是了解神经节苷脂在阿尔茨海默病中的作用，以及它们与记忆障碍的关系，记忆障碍是该疾病最早的认知症状。这项应用的目的是确定饮食中给予GMP是否成功地缓解了5xFAD转基因小鼠模型中阿尔茨海默病的特征。拟议研究的总体假设是，5个月的GMP给药将成功减少成年突变小鼠的斑块形成，并防止神经退化和记忆障碍。在拟议的实验中，将给5xFAD和野生型对照小鼠喂食GMP饮食或对照分离大豆蛋白(ISP)饮食。将评估空间记忆，以及焦虑和感觉运动功能的控制测试。尸检分析将评估与阿尔茨海默氏症相关的神经病理和细胞死亡，以及脂质生物化学。在转基因小鼠中成功减少淀粉样蛋白负担、细胞死亡和记忆损伤，可能为阿尔茨海默病的新治疗策略提供洞察--治疗可以减少或预防阿尔茨海默病患者的痴呆症。 与公共健康相关：拟议的实验将测试食品添加剂糖巨肽(GMP)对记忆和阿尔茨海默病相关神经病理的影响。GMP的使用不仅代表了一种新的治疗策略，也代表了阿尔茨海默病的新治疗靶点。这些实验与国家老龄研究所和国家神经疾病和中风研究所宣布的目标一致。

DESCRIPTION (provided by applicant): Alzheimer's disease is characterized by the aggregation of beta-amyloid (Abeta) protein in the brain, widespread neurodegeneration, and cognitive decline. Our work focuses on amelioration of Alzheimer's pathology and improving memory by modifying brain ganglioside distribution. We have shown that manipulating brain gangliosides in vivo are neuroprotective and reduce amyloid aggregation, and improve behavior in animal models. Although the manipulations differ, they all have in common the ability to increase the levels of GM1 in the brain. GM1 has been shown to be neuroprotective and enhance cognition in many different preparations. A published report with wild-type piglets demonstrates that dietary glycomacropeptide (GMP) improves spatial memory and increases levels of sialylated gangliosides in the brain. Although the study did not report levels of specifi gangliosides, the enhanced cognition suggests that GM1 is elevated. Our goal is to understand the role of gangliosides in Alzheimer's disease and how they relate to memory impairment, the earliest cognitive symptom of the disease. The objective of this application is to determine whether dietary administration of GMP is successful in alleviating features of Alzheimer's disease in the 5xFAD transgenic mouse model. The general hypothesis of the proposed research is that 5 months' administration of GMP will successfully reduce plaque formation and prevent neurodegeneration and memory impairments in adult mutant mice. In the proposed experiments, a GMP diet or control isolated soy protein (ISP) diet will be administered to 5xFAD and wild-type control mice. Spatial memory will be assessed, as well as control tests for anxiety and sensorimotor function. Post-mortem analyses will assess Alzheimer-related neuropathology and cell death, as well as lipid biochemistry. Successfully reducing amyloid burden, cell death, and memory impairment in the transgenic mice may provide insight into new treatment strategies for Alzheimer's disease-- treatments that could reduce or prevent dementia in Alzheimer patients. PUBLIC HEALTH RELEVANCE: The proposed experiments will test the effects of the food additive glycomacropeptide (GMP) on memory and Alzheimer-related neuropathology. The use of GMP represents not only a novel treatment strategy, but a novel therapeutic target for Alzheimer's disease. These experiments are consistent with the stated goals of National Institute on Aging and National Institute of Neurological Disorders and Stroke.