Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet
Introduction
One of the primary features of Alzheimer's disease is neuronal cell loss in the hippocampus and cerebral cortex, areas of the brain involved in memory and cognition. As neurons die, short-term memory fails, followed by a decline in language, reasoning, and the ability to perform everyday tasks. Although the cause of cell death in Alzheimer's disease is not known, considerable evidence implicates β-amyloid (Aβ), a 39–43 amino-acid peptide cleaved from the amyloid precursor protein (APP). Aβ has been shown to induce DNA damage and neuronal death in vitro, and memory deficits in vivo[22], [24], [38], [47]. When APP is overexpressed or abnormally cleaved, Aβ forms toxic oligomers that aggregate into amyloid plaques and are associated with age-related memory impairment [7], [47]. This process has been modeled in several APP-overexpressing transgenic mouse lines bearing mutations linked to familial Alzheimer's disease in humans [9], [14], [30].
Although such genetic factors are sufficient to cause Alzheimer's disease, most cases are sporadic and other potentially-modifiable risk factors may be required for pathogenesis. One such factor is homocysteinemia—elevated plasma levels of the non-protein forming, sulfur amino acid homocysteine. Homocysteinemia is associated with increased risk of Alzheimer's disease and stroke [39], and moderate elevations of plasma homocysteine in cognitively intact individuals are associated with increased risk of subsequent incident dementia [34].
The relationship of homocysteinemia to Alzheimer's disease is uncertain. At high concentrations, homocysteine is neuro- and vasotoxic. In addition, conditions that lead to homocysteinemia have been shown to increase vulnerability to primary brain insults in animal models [8], [40] and to inhibit the proliferation of hippocampal neuroprogenitor cells [19]. The effect of homocysteinemia on cell death has been studied in 10-month-old APP-overexpressing mice bearing the Swedish double mutation (K595N, M596L). Three months of a methyl-donor-free diet supplemented with homocysteine induced a reduction in the number of CA3 pyramidal cells in the APP transgenic mice but not in wild-type controls [18]. The CA1 subfield and soluble amyloid levels were unaffected by the homocysteinemia-inducing diet. It is not known whether the reduction in CA3 cell numbers in the homocysteinemic transgenic mice was due to increased neuronal death or to an inhibitory effect on neural progenitors, or both. Alzheimer's patients have a similar loss of cells in CA3, and lesions of this hippocampal subfield induce memory deficits in experimental animals [3], [11], [32], [35], [37]. The effect of the homocysteinemia-inducing diet on memory and neuropathology in APP-overexpressing mice is not known. The present experiments examined short-term working memory, spatial memory, and neuropathology in Tg2576 transgenic mice exposed to chronic homocysteinemia.
Section snippets
Study population
Female Tg2576 APP-overexpressing transgenic mice bearing the Swedish double mutation (K670N, M671L) were generated on a B6SJLF1 hybrid background [4], [14]. Wild-type X APP transgenic matings were used to produce hemizygous transgenic mice (n = 14) and wild-type littermate controls (n = 19) for all experiments. One transgenic mouse died after hidden-platform training in the water maze, but before cued-platform training. Because the retinal degeneration (rd) gene is known to segregate with the
Short-term working memory is unaffected by genotype or diet
All mice learned to perform the DNMTP task to criterion, and there was no effect of genotype on the rate of learning (data not shown). After 4 months of DNMTP training, mice were matched for performance and placed on the experimental diets. After 5 months on the diets, there was no effect of genotype [F(1,15) = 0.21, p = .651] or diet [F(1,15) = 1.40, p = .255] on the number of trials completed per session, and no Genotype X Diet interaction [F(1,15) = 1.02, p = .329]. This suggests that the diets did not
Discussion
The treatment diet significantly impaired spatial learning and memory in old Tg2576 mice. Age-matched wild-type littermates were unaffected by the same diet. In contrast, short-term working memory was unimpaired in transgenics fed the treatment diet. The cognitive deficit could not be attributed to greater amyloid aggregation, as the treatment diet did not significantly affect plaque load in Tg2576 mice. Thus the combination of Aβ overexpression with long-term dietary metabolic stress that
Acknowledgements
This work was supported by the National Institute of Aging (AG022439), the National Institute of Child Health and Development (HD015052), and the U.S. Department of Agriculture under cooperative agreement No. 58-1950-9-001. Some of the behavioral experiments were conducted within the Murine Neurobehavioral Laboratory core facility (www.medschool.mc.vanderbilt.edu/mnl).
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