Effects of glycomacropeptide on memory and Alzheimer-related neuropathology

对记忆的有效评估可能是创作一部小说的最重要的组成部分 阿尔茨海默氏症的治疗。然而，记忆只是行为障碍中的一种 阿尔茨海默氏症患者表现出。他们也有情感和感觉运动缺陷，以及社交问题 行为。与其他过度表达APP的小鼠不同，5xFAD转基因小鼠通过以下方式表现出强大的神经变性 9个月大。像其他阿尔茨海默病模型一样，它们在空间测试中表现出严重的认知缺陷 学习和记忆。然而，5xFAD小鼠表现出许多其他行为异常。例如, 与野鼠一样，它们对笼友表现出更多的社交行为，但不会表现出 某些品系的实验小鼠包括野生型小鼠的理发现象 紧张。尽管已发表的报告显示，5xFAD小鼠在加号迷宫的张开双臂上花费的时间更多， 焦虑减少的迹象，我们已经表明这可归因于习惯性和 第四层胡须桶中抑制性中间神经元的退化(即使闭合的手臂令人厌恶)。我们有 先前的研究表明，在饮食中补充糖巨肽可以降低Aβ和 神经炎症，并改善5xFAD转基因患者的记忆。GMP中的有效成分是唾液酸，一种 一种β结合的关键介体，已被证明当添加到乳汁中时可以改善仔猪的记忆力。一个 许多研究表明，在婴儿时期接受母乳喂养的儿童的认知表现是 比那些用配方奶喂养的孩子要好。这两个来源之间的主要区别 营养成分是唾液酸，母乳中的唾液酸含量是配方奶的4倍。GMP的作用机制 治疗效果尚不清楚，但可能涉及增加神经细胞黏附的聚唾液酸化(PSA) 神经细胞黏附分子(NCAM)，神经保护性GM1神经节苷脂水平升高，或两者兼而有之。在本申请中 我们将确定内源性GMP的非处方药(OTC)来源是否会有相同的 5xFAD转基因动物食物中加入外源GMP的治疗效果。具体来说，我们 将饲喂含有18%GMP的小鼠乳清分离蛋白(WPI+GMP)或不含GMP的WPI(WPI-GMP) 在他们的饮用水中。WPI+GMP中唾液酸的浓度是WPI+GMP的8倍以上 在成熟的母乳中发现。我们预计，接受WPI+GMP的转基因患者会有更好的记忆力， 与对照组相比，社交行为正常化，Aβ和相关神经病理减少。 重要的是，我们预计GMP将具有改善疾病和增强认知的作用。我们有 研究表明，增加GM1神经节苷脂的操作可以减少斑块并防止正在进行的 即使在5xFAD老年小鼠中也有神经变性。这是不寻常的，因为目前治疗阿尔茨海默氏症的方法 疾病只有及早开始才能奏效。在研究结束时，我们预计将显示目前- 现有的非处方药产品可以改善行为，减轻或预防阿尔茨海默氏症相关的神经病理。

A valid assessment of memory is perhaps the most important component of an endeavor to develop a novel treatment for Alzheimer's disease. However, memory is only one of the behavioral impairments that Alzheimer's patients exhibit. They also have affective and sensorimotor deficits, and problems with social behavior. Unlike other APP-overexpressing mice, the 5xFAD transgenics exhibit robust neurodegeneration by 9 months of age. Like other Alzheimer models, they exhibit profound cognitive deficits on tests of spatial learning and memory. However, the 5xFAD mice show a host of other behavioral anomalies. For example, they exhibit much more social behavior toward their cage-mates as do wild-type mice, but do not exhibit the barbering phenomenon characteristic of some strains of laboratory mice, including wild-types of the same strain. Although published reports show that 5xFAD mice spend more time on open arms of a plus maze, indicative of decreased anxiety, we have shown that this is attributable to impaired habituation and degeneration of inhibitory interneurons in layer IV whisker barrels (i.e., making closed arms aversive). We have shown previously that supplementing the diet with glycomacropeptide (GMP) reduces Aβ and neuroinflammation, and improves memory in 5xFAD transgenics. The active ingredient in GMP is sialic acid, a critical mediator of Aβ binding that has been shown to improve memory in piglets when added to their milk. A number of studies have shown that the cognitive performance of children who were breast-fed as infants is superior to that of children who were formula-fed. The primary difference between the two sources of nourishment is sialic acid, with breast milk containing >4 times that of formula. The mechanism of GMP's therapeutic effects is not known but may involve increased polysialylation (PSA) of neural cell-adhesion molecule (NCAM), increased levels of the neuroprotective GM1 ganglioside, or both. In the present application we will determine whether an over-the-counter (OTC) source of endogenous GMP will have the same therapeutic benefits in 5xFAD transgenics as exogenous GMP incorporated into their chow. Specifically, we will feed mice whey protein isolate (WPI) containing 18% GMP (WPI+GMP) or WPI lacking GMP (WPI-GMP) in their drinking water. The concentration of sialic acid in WPI+GMP is more than eight times higher than that found in mature breast milk. We expect that transgenics receiving WPI+GMP will have better memory, normalized social behavior, and reduced Aβ and associated neuropathology, compared to controls. Importantly, we expect that GMP will have disease-modifying as well as cognitive-enhancing effects. We have shown that manipulations that increase GM1 ganglioside reduce plaque and prevent ongoing neurodegeneration even in aged 5xFAD mice. This is unusual given that current therapies for Alzheimer's disease are only effective when started early. At the end of the study we expect to show that a currently- available OTC product can improve behaviors and attenuate or prevent Alzheimer-related neuropathology.