Figure 6

Working model for tau APF formation. (a) In the proposed mechanism for tau APF formation, tau associated with microtubules (MT) must be released to create an available pool of free soluble tau. Tau then undergoes a conformational change that facilitates misfolding and the formation of oligomers, which can then either proceed along the pathway to form paired helical filaments (PHF) that aggregate and form neurofibrillary tangles (NFTs) or align to form spherical, pore-like structures (APFs). (b) At the cellular level, the formation of these annular structures could occur whenever oligomers are associated in a suitable environment, such as the cell, nuclear, or organelle membranes, allowing for toxic, nonspecific ion leakage.