Tangles, Toxicity, and Tau Secretion in AD – New Approaches to a Vexing Problem

When the microtubule (MT)-associated protein tau is not bound to axonal MTs, it becomes hyperphosphorylated and vulnerable to proteolytic cleavage and other changes typically seen in the hallmark tau deposits (neurofibrillary tangles) of tau-associated neurodegenerative diseases (tauopathies). Neurofibrillary tangle formation is preceded by tau oligomerization and accompanied by covalent crosslinking and cytotoxicity, making tangle cytopathogenesis a natural central focus of studies directed at understanding the role of tau in neurodegenerative disease. Recent studies suggest that the formation of tau oligomers may be more closely related to tau neurotoxicity than the presence of the tangles themselves. It has also become increasingly clear that tau pathobiology involves a wide variety of other cellular abnormalities including a disruption of autophagy, vesicle trafficking mechanisms, axoplasmic transport, neuronal polarity, and even the secretion of tau, which is normally a cytosolic protein, to the extracellular space. In this review, we discuss tau misprocessing, toxicity and secretion in the context of normal tau functions in developing and mature neurons. We also compare tau cytopathology to that of other aggregation-prone proteins involved in neurodegeneration (alpha synuclein, prion protein, and APP). Finally, we consider potential mechanisms of intra- and interneuronal tau lesion spreading, an area of particular recent interest.