Mechanistic and therapeutic perspectives on the role of the Wnt/β-catenin axis in aging and neurodegeneration

Wnt/β-catenin (WβC) signaling plays a fundamental role in maintaining adult brain homeostasis by regulating neurogenesis, mitochondrial function, synaptic integrity, and vascular stability. Beyond its developmental functions, canonical Wnt signaling remains active throughout life, orchestrating neuronal survival and adaptive plasticity. However, aging is accompanied by a gradual decline in Wnt pathway activity, characterized by reduced expression of Wnt ligands (Wnt2, Wnt4, Wnt9a) and mediators (Dvl2, LEF1), alongside increased levels of endogenous inhibitors such as DKK1 and sFRP3. This dysregulation compromises β-catenin stability, weakens antioxidant defense, and enhances susceptibility to oxidative stress and mitochondrial dysfunction, collectively predisposing neurons to degeneration. In neurodegenerative diseases, the suppression of WβC signaling constitutes a unifying molecular signature. In Alzheimer’s disease (AD), Aβ oligomers and DKK1 upregulation inhibit canonical signaling, leading to activation of glycogen synthase kinase-3 beta (GSK-3β), tau hyperphosphorylation, and synaptic loss. Similarly, in Parkinson’s disease (PD), Wnt pathway downregulation and GSK-3β hyperactivity exacerbate dopaminergic neuronal death, mitochondrial failure, and neuroinflammation. Comparable disturbances in β-catenin turnover have been observed in Huntington’s disease and amyotrophic lateral sclerosis, underscoring the widespread contribution of Wnt disruption to neurodegenerative pathology. WβC signaling further engages in intricate crosstalk with pathways such as PI3K/AKT, NF-κB, Notch, and Nrf2, integrating survival, inflammatory, and redox responses. Its modulation determines neuronal resilience under stress conditions. Collectively, these insights highlight WβC signaling as a central hub in the aging brain, where its decline marks the intersection between physiological aging and neurodegeneration. Targeting Wnt pathway components through GSK-3β inhibition, ligand supplementation, or DKK1 antagonism is a promising therapeutic strategy to restore neuronal plasticity and counteract cognitive decline.