Intranasal rapamycin protects against cognitive decline in a mouse model of Down syndrome

Down Syndrome (DS) individuals by the age of 40s are at increased risk to develop Alzheimer's dementia (AD), with deposition of senile plaques and neurofibrillary tangles. Aberrant mTOR signaling in the brain affects multiple pathways including energy metabolism, mitochondrial function, oxidative stress and autophagy, that are key players in age-related cognitive decline and contribute to the development of AD in DS. Our laboratory demonstrated the disturbance of PI3K/Akt/mTOR axis in DS brain, prior and after development of AD. Considering the role of mTOR and its dysregulation in DS, the present study aimed to test the neuroprotective effects of the mTOR inhibitor rapamycin in Ts65Dn mice by setting up a new intranasal delivery protocol (InRapa), that maximizes brain delivery and reduce systemic side effects (12 weeks of treatment). InRapa treatment was able i) to restore mTOR signaling in the hippocampus of Ts65Dn mice and its down-stream targets, including autophagy and insulin signaling, ii) to reduce APP levels, metabolites and processing as well as Tau hyperphosphorylation iii) ultimately resulting in improved cognitive functions, as indexed by radial maze and NOR tests.