Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer’s Disease-like Neuropathology in a Mouse Model for Down Syndrome

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is\r\nstrongly associated with Alzheimer’s disease (AD). Brain insulin resistance greatly contributes to\r\nAD development in the general population and previous studies from our group showed an early\r\naccumulation of insulin resistance markers in DS brain, already in childhood, and even before AD\r\nonset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the\r\nKYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating\r\nthe insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent\r\na promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued\r\ninsulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced\r\noxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of\r\nthe KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1\r\nprotein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide\r\nelicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS\r\ndue to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step\r\nforward in searching for new molecules useful to reduce intellectual disability and counteract AD\r\ndevelopment in DS