RESUMEN
The Wnt pathway stands out as a pivotal signal transduction pathway, operating through two distinct modes of signaling: the canonical/ß-catenin pathway and the non-canonical pathway. Among these, the canonical pathway assumes a paramount role in various physiological and pathological processes within the human body. Particularly in the brain, Wnt exhibits involvement in fundamental physiological events including neuronal differentiation/survival, axonogenesis, neural stem cell regulation, synaptic plasticity, and cell cycle modulation. Notably, scientific evidence underscores the critical role of the Wnt pathway in the pathogenesis of Alzheimer's disease (AD), correlating with its involvement in key pathological features such as tau tangles, Amyloid-ß plaques, synaptic dysfunction, oxidative stress, mitochondrial dysfunction, cognitive impairments, and disruption of the blood-brain barrier integrity. This review aims to comprehensively explore the involvement and significance of Wnt signaling in Alzheimer's. Furthermore, it delves into recent advancements in research on Wnt signaling, spanning from preclinical investigations to clinical trials.
Asunto(s)
Enfermedad de Alzheimer , Vía de Señalización Wnt , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Vía de Señalización Wnt/fisiología , Animales , Progresión de la Enfermedad , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
Dickkopf-1 (DKK1) is a well-characterized Wnt inhibitor and component of the Wnt/ß-catenin signaling pathway, whose dysregulation is associated with multiple abnormal pathologies including osteoporosis, Alzheimer's disease, diabetes, and various cancers. The Wnt signaling pathway has fundamental roles in cell fate determination, cell proliferation, and survival; thus, its mis-regulation can lead to disease. Although DKK1 is involved in other signaling pathways, including the ß-catenin-independent Wnt pathway and the DKK1/CKAP4 pathway, the inhibition of DKK1 to propagate Wnt/ß-catenin signals has been validated as an effective way to treat related diseases. In fact, strategies for developing DKK1 inhibitors have produced encouraging clinical results in different pathological models, and many publications provide detailed information about these inhibitors, which include small molecules, antibodies, and nucleic acids, and may function at the protein or mRNA level. However, no systematic review has yet provided an overview of the various aspects of their development and prospects. Therefore, we review the DKK1 inhibitors currently available or under study and provide an outlook on future studies involving DKK1 and drug discovery.
RESUMEN
In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396.