Down Syndrome (DS) individuals by the age of 40s are at increased risk to develop Alzheimer disease (AD). Several studies demonstrated that memory alterations could be linked to abnormalities in circulating insulin levels and/or defects in insulin signaling pathways. In this scenario, oxidative stress, mitochondrial dysfunction and accelerated aging are likely to act synergistically in promoting AD neuropathology in DS.
The prevalence of diabetes mellitus (T2DM) is higher in DS individuals than in the general population. As T2DM has been identified as a risk factor for AD, the concept developed that drugs that can treat successfully T2DM, such as glucagon like peptide 1 (GLP-1) analogs and inhibitors of its degradation (DPP-4 inhibitors), may also have neuroprotective properties is a promising strategy.
The present project will investigate the link between impaired insulin-pathway and cognition, on a well-established Tg mouse model of DS (Ts65Dn), further proposing DPP-4 as a novel therapeutic target for the prevention of AD in DS population. The neuroprotective effects of sitagliptin, a DPP-4 inhibitor, will be evaluated in DS mice by performing behavioral tests and analysis of insulin-signaling cascade and related pathways. In addition, by proteomics approaches, we will identify brain proteins whose expression levels or post-translational modifications could be significantly modulated by drug treatment. This is the first proposal focused to unravel the potential mechanisms through which impairment of insulin signaling affects cognitive decline in DS. No data on the beneficial role of sitagliptin and other DPP-4 inhibitors administration on learning and memory in DS exist as well as for the role of insulin resistance. The exact mechanisms involved are not fully elucidated and the applicability of drugs already approved for the treatment of diabetes to a broader range of insulin-related pathologies, including AD, needs to be demonstrated.
