Extracellular Protein Quality Control in Tau Pathology

Aging is the primary risk factor for neurodegenerative diseases that are marked by the accumulation of misfolded and aggregated proteins, commonly known as proteinopathies. Among these, tauopathies are the disorders characterized by abnormal tau protein aggregation that are particularly significant in Alzheimer's Disease. Tau protein undergoes pathological post-translational modifications that promote its aggregation into neurofibrillary tangles, which disrupt neuronal function and cognitive decline. Tau can also spread between neurons via extracellular pathways in a prion-like manner, accelerating disease progression. Extracellular protein quality control (PQC) mechanisms modulate this process by balancing tau stability and clearance. However, age-related decline in these PQC systems enhances toxic tau assemblies, their extracellular accumulation and widespread dissemination. This review explores tau secretion, propagation, and extracellular protein quality control (PQC) in maintaining tau homeostasis, aiming to identify therapeutic strategies for tauopathies.