P 116 - Crosstalk between insulin resistance and oxidative stress in the development of Alzheimer-like neurodegeneration

Abstract

Down Syndrome (DS) individuals by the age of 40ys develop a type of dementia that has the same characteristics as Alzheimer disease (AD). Previous studies in DS and AD brain suggest common neurodegenerative pathways including mitochondrial dysfunction, oxidative stress (OS) and reduced glucose metabolism. In addition, several studies suggest a link between insulin resistance and cognitive dysfunction in AD. The present study aims to analyze the crosstalk between the onset of brain insulin resistance (BIR) and OS as possible contributing factors to the neurodegenerative process in tg mouse model of DS (Ts65Dn). We longitudinally analyze (at 1–3-9–18 months) changes of i) IR/IRS1/ERK1/2/Akt levels and activation state iii) oxidative stress markers and iii) biliverdin reductase-A (BVR-A), SIRT1 and PTEN protein levels and activation, in the cortex of Ts65Dn mice. In parallel, changes of APP/Abeta levels have been analyzed. Our results show the mutual interaction between increased OS and BIR in Ts65dn, which does not correlate with Abeta levels. We found that OS negatively impacts the activation of insulin cascade since postnatal age that also persists with age. These findings highlight the role of BIR in the onset of AD-like neurodegeneration and suggest that aberrant insulin signaling strongly contributes to cognitive decline also in DS.