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

Antonella Tramutola; Simona Lanzillotta; Giuseppe Aceto; Sara Pagnotta; Gabriele Ruffolo; Pierangelo Cifelli; Federico Marini; Cristian Ripoli; Eleonora Palma; Claudio Grassi; Fabio Di Domenico; Marzia Perluigi; Eugenio Barone

doi:10.3390/antiox12010111

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

Antioxidants (Basel). 2023 Jan 2;12(1):111. doi: 10.3390/antiox12010111.

Authors

Antonella Tramutola¹, Simona Lanzillotta¹, Giuseppe Aceto^{2

3}, Sara Pagnotta¹, Gabriele Ruffolo^{4

5}, Pierangelo Cifelli⁶, Federico Marini⁷, Cristian Ripoli^{2

3}, Eleonora Palma^{4

5}, Claudio Grassi^{2

3}, Fabio Di Domenico¹, Marzia Perluigi¹, Eugenio Barone¹

Affiliations

¹ Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.
² Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
³ Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, 00168 Roma, Italy.
⁴ Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, 00185 Rome, Italy.
⁵ IRCCS San Raffaele Roma, 00163 Rome, Italy.
⁶ Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
⁷ Department of Chemistry, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.

Abstract

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

Keywords: Alzheimer’s disease; DYRK1A; Down syndrome; brain insulin resistance; intellectual disability.

Grants and funding

This work was supported by Fondi Ateneo grant funded by Sapienza University no RM11715C77336E99 and no RG11916B87F55459 to EB; no RM11916B84D24429 and RG12117A8697DCF1 to EP and GR. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No. 952455; and EpiEpiNet to EP and GR. GR was supported by Italian Ministry of Health “Ricerca corrente”.