Tau is a neuronal microtubule-associated initially soluble cytosolic protein that promotes microtubule polymerization and bundling, and is responsible for microtubule stabilization and transport of proteins in axons. Tau is involved in the development and maintenance of the nervous system and the deregulation of its function is associated with neurodegeneration. Intracellular neurofibrillary tangles (NFTs), mainly composed of hyperphosphorylated aggregated tau, is the hallmark of several neurodegenerative diseases collectively termed tauopathies. These include Alzheimer’s disease (AD), progressive supra-nuclear palsy (PSP), frontotemporal dementia (FTD), cortico-basal degeneration (CBD), Pick’s disease, and others, and the causal signiﬁcance of tau in neurodegeneration is apparent from disease-causing autosomal-dominant tau mutations. Multiple lines of evidence suggest that tau, while typically thought of as an intracellular cytosolic protein, can also be found extracellularly where it is believed to play a central role in the spread of tau pathology from one region of the brain to the next.