Early Metabolic Differences in Alzheimer’s Disease Mouse Model and Exercise Intervention Treatment

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that affects the central nervous system (CNS). In this study, we characterized and examined the early metabolic changes of the triple transgenic Alzheimer's disease (3xtg-AD) mouse model. We examined its relationship with the hypothalamus, a key regulator of metabolism in the CNS. We observed that the 3xtg-AD model exhibited significantly increased oxygen consumption as well as food intake before previously reported amyloid plaque formation, indicating that metabolic abnormalities occurred at early on-set in the 3xtg-AD model compared to a background control. Analysis of mRNA expression in the hypothalamus showed increased gene expression of inflammation and apoptosis related genes and decreased gene expression of orexigenic neuropeptide Y (NPY) at 12 weeks. Analysis utilizing immunofluorescence revealed that anorexigenic pro-opiomelanocortin (POMC) neurons were reduced at 24 weeks in 3xtg-AD model. NPY and POMC act as orexigenic and anorexigenic regulators of metabolism in the hypothalamus. Exercise has been known to stimulate positive effects throughout the CNS and has been studied as a possible treatment for many different neurological disease. Our study wanted to understand the effect of exercise on the 3xtg-AD model. Four-weeks of voluntary exercise treatment was sufficient to reduce several inflammation and apoptosis related gene expression in the hypothalamus. Eight- weeks of voluntary exercise in the 3xtg-AD mice increased POMC and NPY neuron populations compared to sedentary conditions. Our results indicated that early on-set of metabolic abnormalities may have contributed to the pathology of AD. These metabolic abnormalities appeared during the same interval with increased inflammation and decreased neuronal populations and key neuropeptides in the hypothalamus.