Agomelatine Prevents Amyloid Plaque Deposition, Tau Phosphorylation, and Neuroinflammation in APP/PS1 Mice

Abstract

Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

“…28 Furthermore, agomelatine, which is a promising candidate for the treatment of AD, could improve cognitive impairment by inhibiting Hes1/Notch1 signaling in mice. 29 Low levels of Id2 were detected in the 5 × FAD mouse model of AD and human cadavers with AD. Id2 upregulation could augment microtubule stabilization through regulating acetylation of α-tubulin lysine 40 and reconstitute axon growth, suggesting a possible beneficial role of Id2 in AD.…”

“…A transcript analysis of the human entorhinal cortex from AD patients revealed increased expression of Hes1 in the disease progression, while Hes5 showed an up‐regulation in the intermediate stage of the disease and drop in severe AD 28 . Furthermore, agomelatine, which is a promising candidate for the treatment of AD, could improve cognitive impairment by inhibiting Hes1/Notch1 signaling in mice 29 . Low levels of Id2 were detected in the 5 × FAD mouse model of AD and human cadavers with AD.…”

Stress and the risk of Alzheimer dementia: Can deconstructed engrams be rebuilt?

“…For instance, escitalopram improved neuropathology but not behavior in animal models of tauopathy 140 . In contrast, fluoxetine 141 and agomelatine 142 reduced behavioral deficits and neuropathological features in animal models of amyloidosis. The effects of fluoxetine depended on GR signaling via the BDNF pathway 54 .…”

Enhancement of neural regeneration as a therapeutic strategy for Alzheimer's disease (Review)

“…In various transgenic (Tg) rodent models, nerve regeneration ability could be improved by external interventions such as treatment with different types of drugs such as escitalopram, trodusquemine, agomelatine, silibinin, esculentoside A and butyrate (18)(19)(20)(21)(22)(23), the transplantation of human NSCs (hNSCs) (24,25) and electrical stimulation (26), which have been proven to increase the number of neuronal precursor cells, and ameliorate the degree of τ-phosphorylation and AD-related memory loss. The effects of different external interventions on inducing nerve regeneration in various Tg rodent models in recent years are summarized in Table I.…”

“…The effects of different external interventions on inducing nerve regeneration in various Tg rodent models in recent years are summarized in Table I. New mature neurons induced by external interventions from the migration of existing NSCs in certain regions or the generation of NSCs can replenish the missing or damaged cells, which contributes to restoring part or even all of the neural network (18)(19)(20)(21)(22)(23)(24)(25)(26).…”