Cortex Of Ts65Dn Mice Research Articles

Restoring microglial and astroglial homeostasis using DNA immunization in a Down Syndrome mouse model

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40.In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ1-11 fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aβ1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities.Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aβ from a young age by slowing the progression of dementia.

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

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.