1. Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease
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Delphine Stephan, Patrizia Giannoni, Sylvie Claeysen, Michel Khrestchatisky, Evelyne Marchetti-Gauthier, François S. Roman, Stéphane D. Girard, Santiago Rivera, Martine Migliorati, Florence Gaven, Joël Bockaert, Kévin Baranger, Sarah Girot, Aix Marseille Université (AMU), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Détection, évaluation, gestion des risques CHROniques et éMErgents (CHROME) / Université de Nîmes (CHROME), Université de Nîmes (UNIMES), Vect-Horus, This work was supported by funding from the CNRS and Aix-Marseille Université, and by grants from the French National Agency for Research to SR and FR (MAD5 ANR-15-CE16-0006) and to MK (PREVENTAD ANR-11-MALZ-0007) and to the DHUNE project supported by A*MIDEX. This work was carried out thanks to the support of the A*MIDEX project (ANR-11-IDEX-0001-02) funded by the ‘‘Investissements d’Avenir’’ French government program, managed by the ANR. It was also supported by a grant from France Alzheimer to SR, and by La Fondation Vaincre Alzheimer grants to SR (#14776), and MK (#13745). Additional support was provided by CNRS, Inserm, University of Montpellier, and the French NationalAgency of Research (ADAMGUARD ANR-12-BSV4-0008) grants to JB and SC and by France Alzheimer and La Fondation Vaincre Alzheimergrants to SC (#12721). KB was granted a research associate fellowship by the French 'Fondation Plan Alzheimer' and postdoctoral support from the LABEX A*MIDEX 'Management des Talents' from Aix Marseille Université., ANR-15-CE16-0006,MAD5,Validation de MT5-MMP comme nouvelle cible thérapeutique dans la maladie d'Alzheimer et mécanismes d'action(2015), ANR-11-MALZ-0007,PREVENTAD,MMP-12 comme marqueur précoce et cible thérapeutique dans la progression de la maladie d'Alzheimer(2011), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-12-BSV4-0008,ADAMGUARD,Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP(2012), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Giannoni, Patrizia, Validation de MT5-MMP comme nouvelle cible thérapeutique dans la maladie d'Alzheimer et mécanismes d'action - - MAD52015 - ANR-15-CE16-0006 - AAPG2015 - VALID, Maladie d'Alzheimer et Maladies Apparentées - MMP-12 comme marqueur précoce et cible thérapeutique dans la progression de la maladie d'Alzheimer - - PREVENTAD2011 - ANR-11-MALZ-0007 - MALZ - VALID, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID, BLANC - Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP - - ADAMGUARD2012 - ANR-12-BSV4-0008 - BLANC - VALID, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Détection, évaluation, gestion des risques CHROniques et éMErgents (CHROME) / Université de Nîmes ( CHROME ), Université de Nîmes ( UNIMES ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Neurobiologie intégrative et adaptative ( NIA ), and Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique ( CNRS )
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0301 basic medicine ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Transgenic mouse model ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Internal medicine ,medicine ,Amyloid precursor protein ,Dementia ,Effects of sleep deprivation on cognitive performance ,Neuroinflammation ,Pharmacology ,Olfactory tubing maze ,Memory impairments ,biology ,Amyloidosis ,[SCCO.NEUR]Cognitive science/Neuroscience ,[SCCO.NEUR] Cognitive science/Neuroscience ,5-HT(4) receptor agonist ,[ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Alzheimer's disease ,medicine.disease ,Entorhinal cortex ,Pharmacotherapy ,3. Good health ,030104 developmental biology ,Endocrinology ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[ SCCO.NEUR ] Cognitive science/Neuroscience ,biology.protein ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
International audience; Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT4receptors (5-HT4Rs) seems very promising. 5-HT4R agonists exert pro-cognitive effects, inhibit amyloid-β peptide (Aβ) production and therefore directly and positively impact AD progression. In the present work, we investigated the effects of RS 67333, a partial 5-HT4R agonist, after chronic administration in the 5xFAD mouse model of AD. 5xFAD male mice and their wild type (WT) male littermates received either RS 67333 or vehicle solution i.p., twice a week, for 2 or 4 months. Cognitive performance was evaluated in a hippocampal-dependent behavioral task, the olfactory tubing maze (OTM). Mice were then sacrificed to evaluate the metabolism of the amyloid precursor protein (APP), amyloidosis and neuroinflammatory processes. No beneficial effects of RS 67333 were observed in 5xFAD mice after 2 months of treatment, while 5xFAD mice treated for 4 months showed better cognitive abilities compared to vehicle-treated 5xFAD mice. The beneficial effects of RS 67333 on learning and memory correlated with the decrease in both amyloid plaque load and neuroinflammation, more specifically in the entorhinal cortex. The most significant improvements in learning and memory and reduction of pathology stigmata were observed after the 4-month administration of RS 67333, demonstrating that treatment duration is important to alleviate amyloidosis and glial reactivity, particularly in the entorhinal cortex. These results confirm the 5-HT4R as a promising target for AD pathogenesis and highlight the need for further investigations to characterize fully the underlying mechanisms of action.
- Published
- 2017
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