David King Hall, #2027
April 19, 2017, 03:00 PM to 12:00 PM
Research in the field of Alzheimer’s disease (AD) often focuses on the early onset form (EOAD); however, the majority of AD cases are late onset (LOAD). The reason for this is the genetic and causal nature of EOAD, and thus relative ease of developing animal models for EOAD. The present study was an attempt to model LOAD in mice by crossing the J20 mouse with the ApoE4 mouse, resulting in J20/E4 offspring. The J20 mouse over expresses human mutated amyloid precursor protein (hAPP) and the ApoE4 mouse expresses the E4 allele of the apolipoprotein- the only known genetic risk factor for the development of LOAD.
In addition to modeling LOAD, the present study was interested in how dietary copper (Cu) and zinc (Zn) manipulation might impact the progression of AD with age. Previous findings from our lab suggest that increased levels of dietary Zn may have negative effects on cognition and memory that mirror the effects of a Cu deficient diet. These negative effects of increased zinc were remediated by adding Cu to the diet. To examine the effects of dietary Cu and Zn on LOAD, J20/E4 mice and C57BL/6J controls were assigned to one of three diet conditions beginning at four months of age: copper control (Cu+), copper deficient (Cu-), and zinc enhanced (Zn+). Mice were tested on a variety of behavioral tasks at six and twelve months of age.
Non-cognitive behaviors are the primary cause of institutionalization among AD patients, yet there are few studies that examine how non-cognitive behaviors contribute to the progression of the disease. Three non-cognitive behaviors were assessed in J20/E4 LOAD mice: nesting, burrowing, and circadian wheel running. Results showed that at six months of age J20/E4 mice were significantly impaired in both their nest building and burrowing ability compared to controls. This effect did not significantly change with age or with diet condition. Circadian wheel running also differed significantly between genotypes at six and twelve months in such a way that control animals began their active wheel running cycle before J20/E4 animals; no effect of diet condition was observed. Because all three observed non-cognitive behaviors were impaired as early as six months of age, and before the development of characteristic plaque pathology, we believe that non-cognitive behavioral deficits may be predictive of clinical onset and that future research is warranted.
Western blot analyses were performed to examine how dietary metal manipulation in LOAD impacts Cu/Zn bioavailability and inflammation. To examine bioavailability, antibodies against superoxide dismutase (SOD) were probed in brain tissue from thirteen-month old mice, revealing no significant difference between genotype or diet condition. To examine inflammation, antibodies against glial fibrillary protein (GFAP) were used; no significant differences in genotype or diet condition were found