Date of Award
Master of Science
Molecular Cellular and Systemic Physiology
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Abeta) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggest that diabetes may be a risk factor for AD and several studies have linked pro-diabetic diets with an acceleration of AD pathology. Consequently, we hypothesized that the 3xTg AD-like mouse model may show impaired glucose tolerance, therefore; we examined whether glucose tolerance was altered in the 3xTg mouse model of AD early in the pathogenesis (prior to Abeta plaques, neurofibrillary tangle sand cognitive decline) and if so, did it persist throughout. Specifically, 1, 2-3, 4-6, 8-10 and 17 month old male 3xTg mice and wild-type counterparts were assessed for fasting glucose levels, glucose tolerance, plasma insulin levels, insulin sensitivity and the neural and behavioral pathological characteristics of AD. At 1 month, 3xTg mice compared to wild-type controls exhibited impaired glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT), a trend for reduced fasting plasma insulin levels at time 0 and significantly reduced fasting plasma insulin levels 15 minutes post glucose bolus suggesting a possible defect in beta cell function. Interestingly, the glucose intolerance was not a consequence of altered food intake or body weight since these parameters were similar between the 3xTg mice and wild-type controls. Moreover, responsiveness to exogenous insulin during the intraperitoneal insulin tolerance test was not significantly different suggesting equivalent insulin sensitivity. During aging both 3xTg mice and controls exhibited exacerbated changes in fasting glucose levels and glucose tolerance. Interestingly, while control animals show an increase in fasting insulin levels with age, 3xTg mice do not. Immunohistochemical staining for 6E10 and Abeta 1-42 revealed only intraneuronal deposition of reaction product in 3xTg mice with no extracellular depositions noted until 14 months of age. Immunoreactivity of p-tau was observed at 1 month in the hippocampus and cortex and worsened throughout the time period examined. Behavioral deficits began to be detected in 3xTg mice relative to wild-type controls at 21 months of age. The islets in the pancreas suggest that at 2-3 months of age 3xTg mice compared to wild-type controls have a significantly lower amount of immunoreactivity for insulin within their islets although islet size did not differ between groups and this persisted throughout all the time points examined (4-6 and 8-10 months). Taken together, these data reveal that the AD-like 3xTg mouse model exhibits a pro-diabetic phenotype early in the development of AD-like pathology and that this metabolic deficit persists throughout their lifespan raising the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis.
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