G-protein coupled receptor chemokine CX3CR1 influences extracellular Tau internalization in Alzheimer's disease.

Alzheimer's Disease is characterized by significant alterations in the cytoskeleton, driven by hyperphosphorylation of the microtubule-associated protein Tau. This modification impairs Tau's ability to stabilize microtubules, leading to structural instability, disrupted axonal transport, and neuronal degeneration. Hyperphosphorylated Tau aggregates into neurofibrillary tangles and oligomers, exacerbating cellular dysfunction. The cytoskeleton, composed of actin filaments, microtubules, and intermediate filaments, is vital for maintaining cellular structure, intracellular transport, and signalling. G-protein coupled receptors, widely expressed in neuroglial cells, play critical roles in neuroinflammation, synaptic pruning, and cytoskeletal dynamics in neurodegenerative diseases. Extracellular Tau species interact with GPCRs, particularly in microglia and astrocytes, triggering neuroinflammatory responses and cytoskeletal remodelling. Key kinases such as Glycogen Synthase Kinase-3β and Cyclin-Dependent Kinase-5 regulate Tau phosphorylation. Hyperactivation of these kinases, influenced by GPCRs signalling pathways, promotes Tau hyperphosphorylation, contributing to Tauopathies. Stress-related GPCRs like CRFR1, β2AR, and AT2R, along with glutamate-driven activation of mGluR2, exacerbate Tau pathology by enhancing kinase activity. Conversely, certain GPCRs, such as mAChRs, can mitigate Tau hyperphosphorylation by inhibiting GSK-3β activity. Understanding the interplay between Tau, GPCRs, and associated signalling pathways provides insights into the molecular mechanisms driving AD and highlights potential therapeutic targets for mitigating Tauopathies and neurodegeneration.