Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging.

Nathan Duval,David Patterson,Guido N Vacano

doi:10.3389/fnagi.2018.00263

Nathan Duval, David Patterson + Show 1 more

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https://doi.org/10.3389/fnagi.2018.00263

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Abstract

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer’s disease. The Ts65Dn mouse is the best characterized model of DS and has many features reminiscent of DS, including developmental anomalies and age-related neurodegeneration. The mouse carries a partial triplication of mouse chromosome 16 containing roughly 100 genes syntenic to human chromosome 21 genes. We hypothesized that there would be differences in brain metabolites with trisomy and age, and that long-term treatment with rapamycin, mechanistic target of rapamycin (mTOR) inhibitor and immunosuppressant, would correct these differences. Using HPLC coupled with electrochemical detection, we identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age. These include homovanillic acid, norepinephrine, and kynurenine. In addition, we demonstrate that prolonged treatment with rapamycin reduces accumulation of toxic metabolites (such as 6-hydroxymelatonin and 3-hydroxykynurenine) in aged mice.

Highlights

Down syndrome (DS) is due to partial or complete trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability, occurring in roughly 1 in 700 live births (Parker et al, 2010; Presson et al, 2013)
A blood sample was taken the week of sacrifice by maxillary venipuncture from each mouse and a subset was sent to UTHSCSA for rapamycin analysis
In addition to homovanillic acid (HVA) and NE, we show changes in metabolites showing a response to rapamycin treatment (Figure 5A)

Summary

Introduction

Down syndrome (DS) is due to partial or complete trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability, occurring in roughly 1 in 700 live births (Parker et al, 2010; Presson et al, 2013). People with DS show many molecular and anatomical changes in the brain, including neuronal loss and the neuroanatomical hallmarks of AD, amyloid-beta plaques and neurofibrillary tangles. These changes occur most notably in hippocampus and cerebellum, and worsen with age resulting in neuroanatomical features of AD by the fourth decade of life. Metabolomics of the Ts65Dn Mouse (Lott and Head, 2001). By the time they reach 65 years of age, 68–80% of individuals with DS tested are diagnosed with dementia (Wiseman et al, 2015). People with DS represent the largest group genetically at risk for developing AD

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