Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer’s disease

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.

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

“…Considering that chronic treatments with RS67333 have already shown their ability to slow down AD pathology and prevent cognitive deficits in mice (36), donecopride opens the door to a previously unidentified class of compounds that could take advantage of the well-known properties of AChE inhibitors, and it could also enhance the serotonergic transmission that seems to be more and more relevant for a cure for AD (40). Undeniably, serotonin signaling is associated with a lowering of Aβ levels in either soluble form or deposits, a decrease that has a positive outcome on cognitive performance in mice and may prevent deleterious amyloid accumulation in AD (40)(41)(42).…”

“…Undeniably, serotonin signaling is associated with a lowering of Aβ levels in either soluble form or deposits, a decrease that has a positive outcome on cognitive performance in mice and may prevent deleterious amyloid accumulation in AD (40)(41)(42). However, activation of 5-HTR (5-HT 2A , 5-HT 2C , and 5-HT 4 ) has been shown to also induce an increase in soluble form of APPα (34,36,43). Whereas the precise identification of the soluble fragment is still pending for 5-HT 2A/2C R, 5-HT 4 R agonists undoubtedly induce the secretion of the neuroprotective sAPPα fragment and the activation on the nonamyloidogenic processing of APP (36).…”

“…However, activation of 5-HTR (5-HT 2A , 5-HT 2C , and 5-HT 4 ) has been shown to also induce an increase in soluble form of APPα (34,36,43). Whereas the precise identification of the soluble fragment is still pending for 5-HT 2A/2C R, 5-HT 4 R agonists undoubtedly induce the secretion of the neuroprotective sAPPα fragment and the activation on the nonamyloidogenic processing of APP (36). Thus, to the symptomatic cholinergic effects, donecopride and related MTDLs should add capacities to impact APP metabolism by activating 5-HT 4 R. Additional in vivo experiments are required to precisely examine the beneficial effect of this two-target combination and whether it could slow down AD progression.…”

“…5-HT 4 R activation induces the nonamyloidogenic processing of APP and sAPPα release in vivo and in vitro (34,35). Interestingly, we have recently shown that the early and chronic administration of RS67333 is able to reduce amyloid plaque formation, and it also prevents cognitive deficits in a transgenic mouse model of AD (36). The in vitro ability of donecopride to promote sAPPα secretion was evaluated on COS-7 cells that were transiently expressing 5-HT 4 R. Similar to RS67333, donecopride induced a clear dose-dependent sAPPα release ( Fig.…”

Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances

“…Therefore, it is crucial to investigate the effects of chronic modulation of both 5-HT 4 R and 5-HT 6 R on memory. Although to date, only one study has assessed the effect of chronic activation of 5-HT 4 R on memory performance, showing that it reversed memory deficits in a transgenic mouse model of AD [46]. A few studies have investigated chronic 5-HT 6 R blockade, they have demonstrated that chronic modulation of 5-HT 6 R has an anti-amnesic effect, reversing age-related deficits in episodic-like memory [47] and reference memory [48], but also pharmacologically-induced deficits in learning [49] and reference memory [39].…”