MK886 ameliorates Alzheimer's disease by activating the PRKCI/AKT signaling pathway

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, associated with oxidative stress, neuronal Apoptosis, and the accumulation of Amyloid-β (Aβ) plaques. Despite advances in understanding AD pathology, effective treatments remain limited. This study aimed to investigate the therapeutic efficacy and underlying molecular mechanisms of MK886, a selective inhibitor of the 5-lipoxygenase pathway, in the context of AD. Network pharmacology analyses were employed to evaluate MK886's potential as a treatment for AD, revealing promising interactions with key molecular targets implicated in the disease. In vitro experiments demonstrated that MK886 effectively mitigated Aβ1-42 oligomer-induced oxidative stress, Apoptosis, and Ferroptosis in mouse hippocampal neuronal cells (HT22). These effects were validated using techniques such as immunofluorescence, JC-1 staining, TUNEL staining, and flow cytometry. In vivo studies involved administering MK886 to APPswe/PS1dE9 (APP/PS1) mice, which resulted in significant improvements in cognitive and emotional functions as assessed by the Y-maze and Morris water maze tests. Histological evaluations, including Nissl staining, immunofluorescence, and immunohistochemistry, revealed that MK886 preserved hippocampal neuron integrity and reduced Aβ deposition. Proteomics and molecular docking analyses identified the PRKCI/Akt signaling pathway as a key mediator of MK886's neuroprotective effects. This finding was further validated through Western blotting experiments incorporating an Akt Inhibitor. Overall, these findings suggest that MK886 holds promise as a potential therapeutic agent for Alzheimer's disease by enhancing neuronal protection and cognitive function through the activation of the PRKCI/Akt pathway.

AKT; Alzheimer's disease; MK886; Oxidative stress; PRKCI.