Effects of glycomacropeptide on memory and Alzheimer-related neuropathology

对记忆的有效评估也许是奋进发展一部小说的最重要组成部分 阿尔茨海默病的治疗方法然而，记忆只是行为障碍之一， 老年痴呆症患者的展览。他们也有情感和感觉运动缺陷，以及社交问题。 行为与其他APP过表达小鼠不同，5xFAD转基因小鼠表现出强烈的神经变性， 9个月大。与其他阿尔茨海默病模型一样，他们在空间认知测试中表现出严重的认知缺陷。 学习和记忆。然而，5xFAD小鼠显示出许多其他行为异常。比如说， 它们对笼友表现出更多的社会行为，就像野生型小鼠一样，但不表现出 某些品系的实验室小鼠（包括其野生型）特有的毛发生长现象 株尽管已发表的报告显示，5xFAD小鼠在十字迷宫的开放臂上花费更多时间， 表明焦虑减少，我们已经表明，这是归因于受损的习惯， IV层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 先前表明，在饮食中补充糖巨肽（GMP）可降低Aβ， 神经炎症，并改善5xFAD转基因动物的记忆力。GMP中的活性成分是唾液酸， Aβ结合的关键介质，当添加到它们的乳汁中时，已显示出改善仔猪的记忆力。一 许多研究表明，婴儿时期接受母乳喂养的儿童的认知能力 上级于配方奶粉喂养的儿童。这两种来源之间的主要区别是 营养成分是唾液酸，母乳中唾液酸含量是配方奶粉的4倍以上。GMP的作用机制 治疗效果尚不清楚，但可能涉及神经细胞粘附的多聚唾液酸化（PSA）增加 分子（NCAM），神经保护性GM 1神经节苷脂水平增加，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（OTC）来源是否具有相同的 在5xFAD转基因动物中作为外源GMP掺入其食物中的治疗益处。我们特别 将喂食含有18% GMP的乳清蛋白分离物（WPI）（WPI+GMP）或缺乏GMP的WPI（WPI-GMP） 在他们的饮用水。WPI+GMP中唾液酸的浓度是WPI+GMP中唾液酸浓度的8倍以上， 在成熟的母乳中发现。我们预计接受WPI+GMP的转基因动物会有更好的记忆力， 与对照组相比，正常化的社会行为和减少的Aβ和相关神经病理学。 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 显示增加GM 1神经节苷脂的操作减少斑块并防止持续的 甚至在年老的5xFAD小鼠中也存在神经变性。这是不寻常的，因为目前治疗阿尔茨海默氏症的方法 疾病只有在早期开始时才有效。在研究的最后，我们希望表明，目前- 现有的OTC产品可以改善行为并减轻或预防阿尔茨海默病相关的神经病理学。

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.