Prion-Like Characteristics of the Microtubule-Associated Protein Tau

Tauopathies are neurodegenerative diseases characterized by neurofibrillary tangles and/or paired helical filaments of the microtubule-associated protein tau in neurons and glia. While most protein misfolding diseases present with a well-defined pathological syndrome that is restricted to specific subsets of neurons, tau pathology is associated with many distinct disease phenotypes. Furthermore, in Alzheimer disease, tau pathology appears to spread inexorably through the central nervous system along neuroanatomical connections. These features are reminiscent of prion diseases, which exhibit considerable phenotypic diversity and spread pathology between tissues and among individuals. Based on Fourier-transform infrared spectroscopy, circular dichroism, fragility, and electron microscopy, wild-type tau can exist in two self-propagating conformations in vitro with distinct secondary structures, strengths, and morphologies that arise via templated conformation change. In addition, tau aggregates, but not monomer, enter cultured C17.2 neural precursor cells and stimulate fibrillization of intracellular tau. When purified from cells, these fibrils are competent to propagate fibrillization in vitro, and the newly aggregated intracellular tau is capable of traveling between co-cultured cells. The prion-like characteristics of tau are relevant to two key features of tauopathy: phenotypic diversity of the sporadic and inherited tauopathies induced by distinct tau conformers, and spread of disease through the brain. They suggest a general pathogenic mechanism for other neurodegenerative diseases linked to fibrillar protein aggregation