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 A? and neuroinflammation, and improves memory in 5xFAD transgenics. The active ingredient in GMP is sialic acid, a critical mediator of A? 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 A? 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.
The proposed experiments will test the effects of a whey protein isolate (WPI) containing glycomacropeptide (GMP) on memory, social behavior, and Alzheimer-related neurodegeneration and neuropathology. The use of modified 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.
