The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease.

Molecular therapy : the journal of the American Society of Gene Therapy 2022 Apr 04

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The development of new therapeutic avenues that target the early stages of Alzheimer's disease (AD) is urgently necessary. A disintegrin and metalloproteinase domain 10 (ADAM10) is a sheddase that is involved in dendritic spine shaping and limits the generation of amyloid-β. ADAM10 endocytosis increases in the hippocampus of AD patients, resulting in the decreased postsynaptic localization of the enzyme. To restore this altered pathway, we developed a cell-permeable peptide (PEP3) with a strong safety profile that is able to interfere with ADAM10 endocytosis, upregulating the postsynaptic localization and activity of ADAM10. After extensive validation, experiments in a relevant animal model clarified the optimal timing of the treatment window. PEP3 administration was effective for the rescue of cognitive defects in APP/PS1 mice only if administered at an early disease stage. Increased ADAM10 activity promoted synaptic plasticity, as revealed by changes in the molecular compositions of synapses and the spine morphology. Even though further studies are required to evaluate efficacy and safety issues of long-term administration of PEP3, these results provide preclinical evidence to support the therapeutic potential of PEP3 in AD. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Stefano Musardo, Sebastien Therin, Silvia Pelucchi, Laura D'Andrea, Ramona Stringhi, Ana Ribeiro, Annalisa Manca, Claudia Balducci, Jessica Pagano, Carlo Sala, Chiara Verpelli, Valeria Grieco, Valeria Edefonti, Gianluigi Forloni, Fabrizio Gardoni, Giovanni Meli, Daniele Di Marino, Monica Di Luca, Elena Marcello. The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease. Molecular therapy : the journal of the American Society of Gene Therapy. 2022 Apr 04;30(7):2474-2490