Activation of 5-HT4 receptors inhibits secretion of β-amyloid peptides and increases neuronal survival

@article{Cho2007ActivationO5,
  title={Activation of 5-HT4 receptors inhibits secretion of $\beta$-amyloid peptides and increases neuronal survival},
  author={Seongeun Cho and Yun Hu},
  journal={Experimental Neurology},
  year={2007},
  volume={203},
  pages={274-278}
}
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95 Citations
Highly Influential Citations
2
Background Citations
35
Methods Citations
3

95 Citations

Chronic 5-HT4 receptor activation decreases Aβ production and deposition in hAPP/PS1 mice
Distinct Functional Effects of Human 5-HT4 Receptor Isoforms on β-Amyloid Secretion
TLDR
It is shown that activation of h5-HT4(d) strongly stimulates the release of sAPPα and concomitantly decreases extracellular Aβ peptides, and that the pathways regulating either β- or γ-secretase may be differentially controlled by 5- HT4 receptor isoforms.
Design, synthesis, and biological evaluation of new 5-HT4 receptor agonists: application as amyloid cascade modulators and potential therapeutic utility in Alzheimer's disease.
TLDR
Two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPalpha) in the cortex and hippocampus of mice and one of these compounds could also inhibit Abeta fibril formation in vitro.
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
TLDR
The results strongly highlight this 5-HT4 receptor agonist as a promising disease modifying-agent for Alzheimer’s disease.
5-HT4 receptors constitutively promote the non-amyloidogenic pathway of APP cleavage and interact with ADAM10.
TLDR
A new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing is described.
5-HT₄ receptor stimulation leads to soluble AβPPα production through MMP-9 upregulation.
TLDR
It is demonstrated that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves AβPP through α-secretase-like activity, leading to an increase of sAβPPα levels and a reduction of Aβ load.
Regulation of Amyloid Precursor Protein Processing by Serotonin Signaling
TLDR
Chemical and siRNA inhibition is used to identify the proteins which mediate 5-HT4d receptor-stimulated α-secretase activity in the SH-SY5Y human neuronal cell line and shows that G protein and Src dependent activation of phospholipase C are required for α- secretase activity, while, unexpectedly, adenylyl cyclase and cAMP are not involved.
A Novel in vivo Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HT4R) Agonist and Serotonergic Subtype 6 Receptor (5-HT6R) Inverse Agonist Activities, With a Potential Interest Against Alzheimer’s Disease
TLDR
5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα, which could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD.
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
Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro
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References

SHOWING 1-10 OF 26 REFERENCES
The Human Serotonin 5-HT4 Receptor Regulates Secretion of Non-amyloidogenic Precursor Protein*
TLDR
5-HT enhanced the level of secreted sAPPα in a time- and dose-dependent manner in Chinese hamster ovary cells stably expressing the h5- HT4(e) receptor isoform, and inhibition of protein kinase A by H89 potentiated the 5-HT-induced increase in both secreted and cellular sAPP α.
Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
TLDR
Data are supportive of a role of β-amyloid in the impairment of CFC in Tg2576 mice and suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.
M1 Muscarinic Agonists as Potential Disease‐Modifying Agents in Alzheimer's Disease: Rationale and Perspectives
TLDR
The effects on tau proteins suggest a link between M1 mAChR‐mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule‐associated protein, which may indicate a dual role for M1 agonists: as inhibitors of two “vicious cycles,” one induced by β‐amyloids, and the other due to overactivation of certain kinases or downregulation of phosphatases.
Treatment with the Selective Muscarinic Agonist Talsaclidine Decreases Cerebrospinal Fluid Levels of Total Amyloid β‐Peptide in Patients with Alzheimer's Disease
TLDR
It is concluded that treatment with selective M1 agonists may reduce Aβ production and may thus be further evaluated as a potential amyloid‐lowering therapy of AD.
Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory
Mechanisms of ß-Amyloid Neurotoxicity: Perspectives of Pharmacotherapy
TLDR
Although a clinically relevant neuroprotective strategy is not yet available, sequential combination of drug regimens may provide prospects for effective antagonism of late-life Abeta burden and subsequent development of dementia.
β-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease
TLDR
Aβ reduction by active or passive Aβ immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer's disease, and strongly support a direct causative role of Aβ in the synaptic degeneration seen in Alzheimer’s disease.
Evidence for involvement of central 5-HT(4) receptors in cholinergic function associated with cognitive processes: behavioral, electrophysiological, and neurochemical studies.
TLDR
The findings suggest that the functional interaction between the serotonergic system mediated via 5-HT(4) receptors and the cholinergic system associated with cognitive processes exists in vivo.
APPSW Transgenic Mice Develop Age‐related Aβ Deposits and Neuropil Abnormalities, but no Neuronal Loss in CA1
TLDR
It is concluded that Aβ is not acutely neurotoxic, but can disrupt neuronal processes and provoke an inflammatory response, similar to human senile plaques.
Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain
TLDR
It is demonstrated that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Aβ42 with time in culture, and that A β42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, which are associated with pathological alterations within processes and synaptic compartments in Tg 2576 mouse and human AD brains.
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