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Published on: May 28, 2017
Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer's Disease
Tengfei Li1, Elodie Martin1, Yah-Se Abada1
1ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France.
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.
Insights
Masitinib improved cognitive function in Alzheimer's disease mice by protecting synapses, not by reducing amyloid plaques. Mast cell inhibition appears key to its therapeutic effects.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Masitinib is a tyrosine kinase inhibitor targeting mast cells.
- Previous studies suggest masitinib has cognitive benefits in Alzheimer's disease patients.
Purpose of the Study:
- To investigate the mechanism of action of masitinib in Alzheimer's disease.
- To elucidate the role of mast cells in masitinib's therapeutic effects.
Main Methods:
- Administered masitinib to APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease.
- Assessed spatial learning, amyloid-β loads, neuroinflammation, and synaptic markers.
- Investigated effects of complete mast cell depletion in these mice.
Main Results:
- Masitinib treatment restored normal spatial learning in Alzheimer's model mice.
- No significant changes were observed in amyloid-β loads or neuroinflammation.
- Masitinib promoted recovery of synaptic markers, an effect mimicked by mast cell depletion.
Conclusions:
- Masitinib's therapeutic efficacy in Alzheimer's disease may stem from synapto-protective actions.
- Inhibition of mast cells is a critical component of masitinib's beneficial effects.
