Regulation of Wnt/β-catenin Signaling by Presenilin-1 in Alzheimer’s Disease: An Experimental and Theoretical Investigation
Alzheimer’s disease is characterized by the presence of amyloid-beta plaques and hyper-phosphorylated Tau protein tangles. Missense mutations in presenilin-1 gene increases the amyloid-β production and accumulation. Presenilin-1 (PSEN1) has been known to interact with β-catenin, an intracellular protein that forms a part of Wnt signaling pathway and is implicated in neuronal synapse regulation and remodeling. However, the pathological cascade and the biological significance of the interaction between β-catenin and PSEN1 are still debated. There are some evidences that PSEN1 forms complex with β-catenin and up regulates it by increasing its stability. However, there are also conflicting studies that have found down-regulation of Wnt signaling in Alzheimer’s disease. A decrease in β-catenin concentration could result in tau hyper-phosphorylation via GSK-3, a negative regulator of β-catenin. This interaction could link mutations in presenilin-1 gene to tangle pathology. However, there are also studies that show that PSEN1 activates GSK-3 independent of β-catenin and leads to tau hyper-phosphorylation. Thus, PSEN1 appears to stabilize, destabilize β-catenin and/or interact with tau independent of β-catenin. Remarkably, clinical studies of PSEN1 mutations that cause Alzheimer's disease have shown to affect β-catenin stability positively or negatively. Given these contradictory results, it remains unclear how exactly does PSEN1 and β-catenin interact. To elucidate this pathological cascade between the two systems, we propose an experimental and theoretical approach. We incorporate a recently published study of Wnt signaling pathway with PSEN1 activity model to understand how PSEN1 affects β-catenin concentration. Additionally, we use parameter values based on mammalian system unlike the previous models, which use parameters based on non-mammalian system giving us a better ability to interpret the result in mammalian context. We find that when Wnt signaling is activated, β-catenin, its target genes and its negative regulators all have a unique oscillating kinetics that changes to conditions they are exposed. These unique oscillation characteristics can be compared with protein kinetics derived from PSEN-1 and β-catenin knockdown experiments. We use two different targeted genome-editing tools to create PSEN1 and β-catenin knockdown. Successful completion of the knockdown would enable us to compare our theoretical β-catenin degradation kinetics with experimentally derived result giving us a better picture of the interaction between the two cascade. In this context, drug targets aimed at rescuing the disrupted Wnt signaling cascade may prove to be a constructive therapeutic strategy for Alzheimer’s disease.