Wnt Signaling Dynamics in Neurodegenerative Disease Mechanisms
Summary
Wnt signalling encompasses a network of secreted glycoproteins and their receptors, which orchestrate fundamental processes in the nervous system from embryonic patterning to synaptic plasticity in the adult brain. In its canonical form, Wnt ligands bind Frizzled receptors and the co-receptor LRP6 to stabilise β-catenin, enabling transcriptional programmes that support neuronal survival, synapse formation and neurogenesis. Non-canonical cascades, including the planar cell polarity (PCP) pathway, regulate cytoskeletal dynamics and spine morphology. Deregulation of Wnt signalling has emerged as a unifying feature of neurodegenerative disorders, notably Alzheimer’s disease, where deficits in canonical activity contribute to amyloid-β accumulation, tau hyperphosphorylation and blood–brain barrier breakdown. Aberrant expression of antagonists such as Dickkopf-1 exacerbates synaptic vulnerability by inhibiting both β-catenin-dependent and PCP pathways. Recent advances highlight the dynamic interplay between Wnt components and other pathogenic cascades, underscoring the potential of pathway restoration to promote circuit resilience and cognitive function across a spectrum of age-related neurological conditions.
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Technical terms
Wnt signalling: a set of secreted proteins that engage surface receptors to regulate cell fate, synaptic function and neuronal survival.
β-catenin pathway: the canonical Wnt cascade in which ligand binding stabilises β-catenin, permitting its nuclear role in gene regulation.
Frizzled receptor: a seven-transmembrane receptor that recognises Wnt ligands and initiates intracellular signalling cascades.
LRP6: a co-receptor partnering with Frizzled to activate canonical Wnt/β-catenin signalling.
Dickkopf-1 (Dkk1): a secreted inhibitor that binds LRP6, blocking both canonical and non-canonical Wnt pathways.
References
- Wnt Signaling Deregulation in the Aging and Alzheimer’s Brain. Frontiers in Cellular Neuroscience (2019).
- A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease. Science Advances (2023).
- Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease. Molecular Brain (2019).
- Amyloid β synaptotoxicity is Wnt‐PCP dependent and blocked by fasudil. Alzheimer's & Dementia (2017).
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