Alzheimer's disease: Extracellular Tau internalization in neuro-glial axis and its propagation mechanisms.

Tau is a protein associated with microtubules that is essential to the central nervous system's extracellular and intracellular functions. Aberrant post-translational changes cause Tau to dissociate from microtubules in pathological circumstances like Tauopathies and also in AD (AD). The free Tau can diffuse into the extracellular space, contributing to neurofibrillary tangles formation and paired helical filaments. Moreover, pathogenic Tau can spread in a prion-like manner from diseased neurons to healthy ones exacerbating Tau pathology. By stimulating the NLRP3 inflammasome and other pathways, extracellular Tau has an impact on microglia. This, in turn, triggers inflammatory responses and leads to neuroinflammation. Astrocytes, the predominant brain cells, absorb extracellular Tau and undergo morphological and functional changes that result in the production of neurotoxic compounds, which ultimately cause neurodegeneration. The uptake of Tau by astrocytes results in a proinflammatory phenotype and cellular senescence, which intensify neuroinflammatory processes and oxidative stress and accelerate the advancement of neurodegenerative illnesses.