Tau Strains and Their Propagation in Experimental Disease Models

Tauopathies encompass a broad family of neurodegenerative diseases, including Alzheimer’s disease, which are characterized by the fibrillization of the microtubuleassociated tau protein. The normal function of tau is to stabilize and promote the assembly of microtubules in neuronal axons. Sequestration of tau into amyloid fibrils results in destabilization of the microtubule network and may contribute to disease progression. As tau is an intracellular protein and proteins do not passively cross cell membranes, tau fibril formation has been assumed to occur spontaneously within individual cells. However, recent evidence suggests that tau shares several characteristics with prions, which propagate through the brain by protein-protein interactions in the interstitial space; these characteristics include conformational templating of native tau into disease-associated fibrils and intercellular fibril propagation. Tau adopts diverse fibril structures, or strains, which have been shown to self-propagate in the presence of monomeric recombinant tau protein. Exogenous tau fibrils induce misfolding of native tau in both cell culture and animal models, causing strain-dependent cellular dysfunction and differential patterns of neuropathology. Tau fibers have also been found recently in patient samples or models of several diseases not formerly identified as tauopathies, including chronic traumatic encephalopathy, Parkinson’s disease, and Huntington’s disease, suggesting a common underlying mechanism for neurodegenerative diseases. The possibility that tauopathies and other neurodegenerative diseases involve prion-like mechanisms has implications for studies designed to understand disease pathogenesis and for the development of therapies, which may be devised to impede tau strain propagation and intercellular transmission, allowing clearance of tau fibrils and potentially halting or reversing disease progression.  E-mail address: [email protected] Kyle P. McHugh, Olga A. Morozova and David W. Colby 158