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2 results on '"Youssef, Ihsen"'

1. Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer's Disease.

Author

Li T, Martin E, Abada YS, Boucher C, Cès A, Youssef I, Fenaux G, Forand Y, Legrand A, Nachiket N, Dhenain M, Hermine O, Dubreuil P, Delarasse C, and Delatour B

Subjects
Alzheimer Disease genetics, Amyloid beta-Peptides pharmacology, Amyloid beta-Protein Precursor genetics, Animals, Benzamides, Disease Models, Animal, Male, Mice, Transgenic, Piperidines, Presenilin-1 genetics, Presenilin-1 pharmacology, Pyridines, Thiazoles administration & dosage, Alzheimer Disease drug therapy, Cognition drug effects, Synapses drug effects, Thiazoles pharmacology
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.

Published
2020
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2. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease.

Author

Garcia P, Youssef I, Utvik JK, Florent-Béchard S, Barthélémy V, Malaplate-Armand C, Kriem B, Stenger C, Koziel V, Olivier JL, Escanye MC, Hanse M, Allouche A, Desbène C, Yen FT, Bjerkvig R, Oster T, Niclou SP, and Pillot T

Subjects
Alzheimer Disease genetics, Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides pharmacology, Amyloid beta-Protein Precursor genetics, Animals, Apoptosis genetics, Brain pathology, Cell Count methods, Cell- and Tissue-Based Therapy methods, Cells, Cultured, Ciliary Neurotrophic Factor administration & dosage, Disease Models, Animal, Enzyme Inhibitors pharmacology, Enzyme-Linked Immunosorbent Assay methods, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Green Fluorescent Proteins genetics, Humans, Male, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, Neurons drug effects, Neurons metabolism, Peptide Fragments administration & dosage, Peptide Fragments pharmacology, Signal Transduction drug effects, Synapses metabolism, Synaptosomes metabolism, Synaptosomes pathology, Synaptosomes ultrastructure, Time Factors, Transfection methods, Alzheimer Disease complications, Ciliary Neurotrophic Factor biosynthesis, Ciliary Neurotrophic Factor therapeutic use, Memory Disorders etiology, Memory Disorders therapy, Synapses drug effects
Abstract

The development of novel therapeutic strategies for Alzheimer's disease (AD) represents one of the biggest unmet medical needs today. Application of neurotrophic factors able to modulate neuronal survival and synaptic connectivity is a promising therapeutic approach for AD. We aimed to determine whether the loco-regional delivery of ciliary neurotrophic factor (CNTF) could prevent amyloid-beta (Abeta) oligomer-induced synaptic damages and associated cognitive impairments that typify AD. To ensure long-term administration of CNTF in the brain, we used recombinant cells secreting CNTF encapsulated in alginate polymers. The implantation of these bioreactors in the brain of Abeta oligomer-infused mice led to a continuous secretion of recombinant CNTF and was associated with the robust improvement of cognitive performances. Most importantly, CNTF led to full recovery of cognitive functions associated with the stabilization of synaptic protein levels in the Tg2576 AD mouse model. In vitro as well as in vivo, CNTF activated a Janus kinase/signal transducer and activator of transcription-mediated survival pathway that prevented synaptic and neuronal degeneration. These preclinical studies suggest that CNTF and/or CNTF receptor-associated pathways may have AD-modifying activity through protection against progressive Abeta-related memory deficits. Our data also encourage additional exploration of ex vivo gene transfer for the prevention and/or treatment of AD.

Published
2010
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