Abstract
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.
Highlights
Alzheimer’s disease (AD) is currently recognized as one of the most socially devastating neurodegenerative disorders (Ferri et al, 2005)
Immunohistochemical assessment of astroglial and microglial activation showed that RS 67333 chronic treatment strikingly reduced both astrogliosis (49 ± 9% decrease of GFAP staining in hippocampal brain slices of treated animals in comparison to controls that received vehicle; Figures 5A–C) and microgliosis (57 ± 9% reduction of IBA1 staining in treated animals compared to controls; Figures 5D,E)
In this study, we show that early, chronic administration of the 5-HT4 receptor agonist RS 67333 reduces the amyloid burden and inflammation markers and prevents memory impairment in 5XFAD mice
Summary
Alzheimer’s disease (AD) is currently recognized as one of the most socially devastating neurodegenerative disorders (Ferri et al, 2005). According to the amyloid cascade hypothesis, Aβ peptides and in particular the oligomeric forms are critical determinants of synaptic loss and cognitive deficits in AD (Hardy and Selkoe, 2002) In line with this theory, recent results from Phase III clinical trials indicate that Solanezumab, an anti-Aβ monoclonal antibody, can bring some cognitive benefit to patients with mild AD-related dementia (Aisen et al, 2013), while late interventions were unsuccessful (Sperling et al, 2013). We tested the hypothesis that chronic administration of the 5-HT4 receptor agonist RS 67333 may shift APP cleavage toward sAPPα production, inhibiting amyloid formation and improving the cognitive performance in 5XFAD mice, a model of AD (Oakley et al, 2006). Our results suggest that this 5-HT4 receptor agonist efficiently slows down amyloidogenesis during the prodromal-like stage of the pathology and highlight the importance of early intervention to enhance the chances of significant therapeutic effects
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