The effects of exercise on hypothalamic neurodegeneration of Alzheimer’s disease mouse model

Abstract

Alzheimer’s disease is a neurodegenerative disorder that affects the central nervous system. In this study, we characterized and examined the early metabolic changes in the triple transgenic mouse AD model (3xtg-AD), and their relationship with the hypothalamus, a key regulator of metabolism in the central nervous system. We observed that the 3xtg-AD model exhibited significantly higher oxygen consumption as well as food intake before reported amyloid plaque formation, indicating that metabolic abnormalities occurred at early onset in the 3xtg-AD model compared with their counterparts. Analysis of gene expression in the hypothalamus indicated increased mRNA expression of inflammation- and apoptosis-related genes, as well as decreased gene expression of Agouti-related protein (AgRP) and Melanocortin 4 receptor (MC4R) at 12 weeks of age. Immunofluorescence analysis revealed that pro-opiomelanocortin (POMC) and NPY-expressing neurons decreased at 24 weeks in the 3xtg-AD model. Four weeks of voluntary exercise were sufficient to reverse the gene expression of inflammation and apoptotic markers in the hypothalamus, six weeks of exercise improved glucose metabolism, moreover, 8 weeks of voluntary exercise training attenuated apoptosis and augmented POMC and NPY-expressing neuronal populations in the hypothalamus compared to the control group. Our results indicated that early onset of metabolic abnormalities may contribute to the pathology of AD, which is associated with increased inflammation as well as decreased neuronal population and key neuropeptides in the hypothalamus. Furthermore, early intervention by voluntary exercise normalized hypothalamic inflammation and neurodegeneration as well as glucose metabolism in the 3xtg-AD model. The data, taken as a whole, suggests a hypothalamic-mediated mechanism where exercise prevents the progression of dementia and of Alzheimer’s disease.

Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

“…In the present study, β3AR agonist induced weight loss in both NonTg and 3xTg-AD mice. Food consumption was higher in 3xTg-AD compared to NonTg mice, an observation previously reported in this model (Adebakin et al, 2012;K. Do et al, 2018), and CL-316,243 increased food intake in NonTg mice.…”

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

“…However, in the brain, MC4R is involved in anorexigenic, ant-inflammatory, and antiapoptotic effects ( Caruso et al, 2013 ). In addition, AD transgenic mouse model 3xTg-AD showed lower levels of MC4R and AgRP mRNA compared to the control ( Do et al, 2018 ), confirming the important role of MC4R in the development of AD.…”

“…Hypothalamic gene expression showed higher mRNA expression of genes related to inflammation and apoptosis, as well as lower levels of POMC and NPY-expressing neurons. However, voluntary exercise training reduced apoptosis and increased POMC and NPY-expressing neuronal populations ( Do et al, 2018 ). Early exercise intervention can normalize hypothalamic inflammation, neurodegeneration, and the glucose metabolism in 3xTg-AD model, suggesting that exercise can reduce the progression of dementia and AD ( Do et al, 2018 ).…”

Role of sex and high fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease

“…In the current study, increased inflammation in the periphery of AD mice (liver, plasma, and visceral fat) mimics trends of increased hypothalamic expression of glial markers Iba1 and GFAP, as well as pro-inflammatory cytokines (TNF-a and IL-1B), in AD males. Previous studies have also reported increased hypothalamic expression of pro-inflammatory markers in 3xTg-AD male mice at even 12 weeks of age [95]. Additionally, free fatty acids from the consumption of a high fat diet can contribute to hypothalamic inflammation [119].…”

“…Other AD rodent models similarly report body weight deficits that become more pronounced with age, as well as decreased body fat, despite similar or even increased food consumption [24,[90][91][92][93][94]. While unclear in clinical populations, findings in mice exhibiting AD pathology suggest that elevated basal metabolic rate (measured by oxygen consumption), rather than increased activity levels, may be contributing to these differences [24,91,92,95]. There are some studies that do show hyperactivity in AD mouse models [93]; however, AD males in the current study did not exhibit increased activity levels in open field testing.…”