Investigation of the role of wnt/β-catenin signaling in development of Alzheimer's disease in a zebrafish model of amyloid-β toxicity

The Wnt/β-catenin signal transduction pathway is evolutionarily conserved and plays a key role in the regulation of development in the embryonic period, synapse formation in adulthood, apoptosis, and adipogenesis. Due to its pleiotropic and basic function, an abnormal activation or disruption in this signaling pathway may be associated with many diseases such as Alzheimer's, cancer, diabetes, and Parkinson's. Alzheimer's disease (AD) is a neurological disease characterized by dementia and loss of synaptic functions and associated with aging. Alzheimer's disease is characterized by three distinctive pathologies: (1) accumulation of extracellular beta-amyloid plaques, (2) accumulation of intracellular Tau clusters, and (3) diffuse cell death seen in advanced Alzheimer's disease. However, synapse losses that can be seen in the early course of the disease represent the most common pathological link of the disease and are the most important cause of cognitive losses. Current animal models suggest that this synapse degeneration and loss is triggered by accumulating Aβ oligomers. Intercellular accumulation of this oligomer, which is very important for synaptic stabilization and function, causes deregulation of Wnt signaling pathways. This deregulation of the Wnt signaling pathway triggers synapse degeneration and leads to damping in synapse functions. This disruption in the signaling pathway is a trigger for the further progression of AD. In the scope of the thesis, Alzheimer's disease, which can be triggered by the Aβ42 peptide, was modeled using adult transgenic (6XTCF) zebrafish. Zebrafish have genes orthologous to some human genes thought to play an important role in Alzheimer's disease. Throughout the thesis, Aβ42 was injected into the brains of adult zebrafish using the CVMI technique, and a model of Alzheimer's disease was created. The regenerative response of zebrafish to toxicity was analyzed by qPCR and confocal microscopy. The change in AD pathogenesis was investigated in zebrafish treated with IWR-1 drug on days of high regeneration. As a result, more Aβ accumulation and cell loss were observed in zebrafish treated with IWR-1. Key Words: WNT/β-CATENIN, Zebrafish, Alzheimer's Disease