Cognitive Activity Effects on Neuropathology & Dementia

There is evidence to suggest that engaging in cognitively-stimulating activities may ameliorate the dementa of Alzheimer’s disease or delay or prevent its onset. However, an alternate explanation for these data is that some people have mild cognitive impairments even very early in life, and that these people are less likely to engage in cognitively-stimulating activities and may be more susceptible to Alzheimer’s disease, or a more severe form of the disease. In addition to this uncertainty, it is not known how cognitive activity affects the neuropathology of Alzheimer’s disease, specifically the cell death and formation of plaques in the brains of Alzheimer’s patients. Plaques are one of the two neuropathological features of Alzheimer’s disease, and are thought to contribute to cell death and memory irrq;iairment. The proposed experiments are designed to determine cause-and effect relationships between persistent, daily cognitive activity, and later memory ability and neuropathological features relevant to Alzheimer’s disease, in transgenic mice. The mice harbor a mutant human gene that controls the production of amyloid precursor protein (APP). Humans with this mutant gene invariably get Alzheimer’s disease. The result of having the mutant gene is the formation of plaques in the brains of Alzheimer’s patients and in the APP transgenic mice. Although this mouse is a good model of the plaque formation of Alzheimer’s disease, there is no cell death in the brains of these mice. This is troublesome because there is massive cell death in Alzheimer’s disease, and it is thought to be responsible at least in part for the severe cognitive deficits observed in Alzheimer’s disease. Recently, a new technique was published that will allow us to induce cell death in the transgenic mice selectively in a brain area involved in memory processing. The technique involves feeding the mice a diet deficient in folic acid (folate) and with added homocysteine. Normal mice do not get cell death when fed this diet. Because this technique of inducing cell death is new, there is no evidence showing that it will impair memory further in APP transgenic mice Thus the first Aim of this proposal is to determine whether a folate-deficient diet impairs memory in APP transgenic mice. (These mice will also be used in the second Aim to determine whether engaging in cognitively-stimulating activity improves memory or Alzheimer-like neuropathology.) Two experiments will be conducted to determine whether folate deficiency further impairs memory in APP transgenic mice. The first experiment will determine the effect of folate deficiency on mice that have already learned a complex memory test to a high degree of proficiency. In this experiment, mice will be trained on a complex cognitive task starting at 9 months of age–before plaque formation begins. They will perform this difficult memory task every day for 6 months, motivated by food reinforcement. (Mice are restricted to 4 hours of food access per day, immediately after performing the memory task. Under this regimen they still gain weight but are motivated to work for food). During the six months of performing this memory task, the APP transgenic mice will develop a significant amount of plaque in the brain. At 12 months of age, half of the transgenic and half of the normal mice will be fed a folate-deficient diet for 3 months. Two weeks before the mice reach 15 months of age, half of the mice in each of the four groups will perform an additional battery of memory tasks that are unlike the complex memory test they had been performing. By 15 months of age there will be significant cell death in the brains of APP transgenic mice fed the folate-deficient diet, and we expect their memory performance to be worse too. The second experiment in the first Aim will determine whether memory is impaired in mice that already have significant plaque formation and have already had the folate-deficient diet for 2.5 months. These mice will sit in their home cages and not be on food restriction, until 14.5 months of age. At that time a battery of memory tests will be conducted to determine the effect of significant plaque formation plus cell death. This is the same battery performed by some of the mice in the first experiment, and we call it our “”memory battery””. The tests take 2 weeks to conduct. Our second aim is designed to determine whether mice with cognitive training