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

NEUROPHARMACOLOGY

卷:126

Article

Baranger, Kevin¹  Giannoni, Patrizia^2,3  Girard, Stephane D.^1,4  Girot, Sarah¹  Gaven, Florence²  Stephan, Delphine¹  Migliorati, Martine¹  Khrestchatisky, Michel¹  Bockaert, Joel²  Marchetti-Gauthier, Evelyne¹  Rivera, Santiago¹  Claeysen, Sylvie²  Roman, Francois S.¹ 

[1] Aix Marseille Univ, CNRS, NICN, Marseille, France

[2] Univ Montpellier, IGF, CNRS, INSERM, F-34094 Montpellier, France

[3] Univ Nimes, EA7352, Equipe Chrome, F-30000 Nimes, France

[4] Vect Horus SAS, Fac Med Secteur Nord, CS80011,Blvd Pierre Dramard, F-13344 Marseille 15, France

关键词: 5-HT4 receptor agonist;    Alzheimer's disease;    Memory impairments;    Olfactory tubing maze;    Transgenic mouse model;    Pharmacotherapy;   

DOI  :  10.1016/j.neuropharm.2017.08.031

来源: Elsevier

【 摘 要 】

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-HT4 receptors (5-HT(4)Rs) seems very promising. 5-HT4R agonists exert pro-cognitive effects, inhibit amyloid-beta peptide (A beta) 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free