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.

The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease / S. Musardo, S. Therin, S. Pelucchi, L. D'Andrea, R. Stringhi, A. Ribeiro, A. Manca, C. Balducci, J. Pagano, C. Sala, C. Verpelli, V. Grieco, V. Edefonti, G. Forloni, F. Gardoni, G. Meli, D. Di Marino, M. Di Luca, E. Marcello. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 30:7(2022 Jul 06), pp. 2474-2490. [10.1016/j.ymthe.2022.03.024]

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

S. Musardo
Primo
;
S. Therin
Secondo
;
S. Pelucchi;L. D'Andrea;R. Stringhi;C. Verpelli;V. Grieco;V. Edefonti;F. Gardoni;M. Di Luca
Penultimo
;
E. Marcello
Ultimo
2022

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-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.
ADAM10; Alzheimer's disease; cell-permeable peptide; cognitive deficits; endocytosis; sAPPα; synapse; synaptic dysfunction
Settore BIO/14 - Farmacologia
   Synaptic Dysfunction in Alzheimer Disease
   SyDAD
   EUROPEAN COMMISSION
   H2020
   676144

   Deciphering the role of ADAM10 and CAP2 in Age‐related Accumulation of deficits
   COCOON
   FONDAZIONE CARIPLO
   2018-0511

   Identification and validation of COmmon pathways at the CrOssrOads of neurodegeneration and Neuroprotection (COCOON)
   PerMedNet
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2017MYJ5TH_001

   Study of the crosstalk between multiple pathways in the regulation of inflammatory processes in models of chronic and degenerative diseases
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2017B9NCSX_004

   Medicina personalizzata per strategie innovative in malattie neuro-psichiatriche e vascolari (PerMedNet)
   PerMedNet
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   ARS01_01226
6-lug-2022
4-apr-2022
Article (author)
File in questo prodotto:
File Dimensione Formato  
Musardo et al.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 3.3 MB
Formato Adobe PDF
3.3 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/925110
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 15
  • ???jsp.display-item.citation.isi??? 11
social impact