Tengfei Li1, Elodie Martin1, Yah-Se Abada1, Céline Boucher1, Aurélia Cès1, Ihsen Youssef1, Grégory Fenaux2, Yona Forand2, Annaelle Legrand2, Nadkarni Nachiket3,4, Marc Dhenain3,4, Olivier Hermine5, Patrice Dubreuil2, Cécile Delarasse1,6, Benoît Delatour1. 1. ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France. 2. CRCM, [Signaling, Hematopoiesis and Mechanism of Oncogenesis, Equipe Labellisée Ligue Contre le Cancer], Inserm, U1068; Institut Paoli-Calmettes; Aix-Marseille Univ, UM105; CNRS, UMR7258, Marseille, France. 3. Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France. 4. Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut François Jacob, MIRCen, Fontenay-aux-Roses, France. 5. Department of Hematology, INSERM UMR1163 and CNRS URL 8254, Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Necker Children's Hospital, APHP, Paris, France. 6. Sorbonne Université, Inserm, CNRS, Institut de la Vision, 17, Paris, France.
Abstract
BACKGROUND: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer's disease. OBJECTIVE: We aimed to shed light on the mode of action of masitinib in Alzheimer's disease. METHODS/ RESULTS: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic impairments. CONCLUSION: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition.
BACKGROUND:Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer's disease. OBJECTIVE: We aimed to shed light on the mode of action of masitinib in Alzheimer's disease. METHODS/ RESULTS: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic impairments. CONCLUSION: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition.
Authors: Paloma A Harcha; Polett Garcés; Cristian Arredondo; Germán Fernández; Juan C Sáez; Brigitte van Zundert Journal: Int J Mol Sci Date: 2021-02-15 Impact factor: 5.923