Amyloid β (Aβ) accumulation is considered the main culprit in the pathogenesis 
of Alzheimer's disease (AD). Recent studies suggest that decreasing Aβ 
production at very early stages of AD could be a promising strategy to slow down 
disease progression. Serotonin 5-HT4 receptor activation stimulates α-cleavage 
of the amyloid precursor protein (APP), leading to the release of the soluble 
and neurotrophic sAPPα fragment and thus precluding Aβ formation. Using the 
5XFAD mouse model of AD that shows accelerated Aβ deposition, we investigated 
the effect of chronic treatments (treatment onset at different ages and 
different durations) with the 5-HT4 receptor agonist RS 67333 during the 
asymptomatic phase of the disease. Chronic administration of RS 67333 decreased 
concomitantly the number of amyloid plaques and the level of Aβ species. 
Reduction of Aβ levels was accompanied by a striking decrease in hippocampal 
astrogliosis and microgliosis. RS 67333 also transiently increased sAPPα 
concentration in the cerebrospinal fluid and brain. Moreover, a specific 5-HT4 
receptor antagonist (RS 39604) prevented the RS 67333-mediated reduction of the 
amyloid pathology. Finally, the novel object recognition test deficits of 5XFAD 
mice were reversed by chronic treatment with RS 67333. Collectively, these 
results strongly highlight this 5-HT4 receptor agonist as a promising disease 
modifying-agent for AD.