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-b. 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 ac-tivity of ADAM10. After extensive validation, experiments in a relevant animal model clarified the optimal timing of the treat-ment 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 syn-aptic plasticity, as revealed by changes in the molecular compo-sitions of synapses and the spine morphology. Even though further studies are required to evaluate efficacy and safety is-sues of long-term administration of PEP3, these results provide preclinical evidence to support the therapeutic potential of PEP3 in AD.
The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease / Musardo, S., Therin, S., Pelucchi, S., D'Andrea, L., Stringhi, R., Ribeiro, A., Manca, A., Balducci, C., Pagano, J., Sala, C., Verpelli, C., Grieco, V., Edefonti, V., Forloni, G., Gardoni, F., Meli, G., Di Marino, D., Di Luca, M., Marcello, E.. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 30:7(2022), pp. 2474-2490. [10.1016/j.ymthe.2022.03.024]
The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease
Di Marino, Daniele;
2022-01-01
Abstract
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-b. 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 ac-tivity of ADAM10. After extensive validation, experiments in a relevant animal model clarified the optimal timing of the treat-ment 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 syn-aptic plasticity, as revealed by changes in the molecular compo-sitions of synapses and the spine morphology. Even though further studies are required to evaluate efficacy and safety is-sues of long-term administration of PEP3, these results provide preclinical evidence to support the therapeutic potential of PEP3 in AD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
