Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer’s Disease

Article type: Research Article

Authors: Li, Tengfei^{a; 1} | Martin, Elodie^{a; 1} | Abada, Yah-se^a | Boucher, Céline^a | Cès, Aurélia^a | Youssef, Ihsen^a | Fenaux, Grégory^b | Forand, Yona^b | Legrand, Annaelle^b | Nachiket, Nadkarni^{c; d} | Dhenain, Marc^{c; d} | Hermine, Olivier^e | Dubreuil, Patrice^b | Delarasse, Cécile^{a; f} | Delatour, Benoît^{a; *}

Affiliations: [a] ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France | [b] 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 | [c] Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France | [d] Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut François Jacob, MIRCen, Fontenay-aux-Roses, France | [e] Department of Hematology, INSERM UMR1163 and CNRS URL 8254, Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Necker Children’s Hospital, APHP, Paris, France | [f] Sorbonne Université, Inserm, CNRS, Institut de la Vision, 17, Paris, France

Correspondence: [] Correspondence to: Benoît Delatour, ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Sorbonne Universités, Team “Alzheimer’s and Prion diseases”, 47 bd de l’hôpital, 75013 Paris, France. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer’s disease, cognition, drug evaluation, masitinib, mast cells, preclinical, synapses

DOI: 10.3233/JAD-200466

Journal: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1339-1345, 2020