The Wischik team found that Tau aggregation has the characteristics of a self-sustaining and self-propagating process in vitro and confirmed this in proprietary cell models. Due to the decline in efficiency of the clearance pathways for these Tau aggregates in the neuron through aging, and even more so in Alzheimer’s disease subjects, the Tau aggregates build up in the neuron, leading to neuronal inactivity and eventual death.

Seeding / Nucleation Event
Although the primary cause of Tau aggregation in Alzheimer’s disease is unclear, there is an increasing consensus that an early seeding or nucleation event is required. The Wischik team believes this nucleation event is likely to be generated from certain partially degraded protein products of dysfunctional endosomal-lysosomal metabolism (“ELM”) in the aging neuron . In addition, either Tau mutations or truncated Tau can also directly initiate the Tau aggregation cascade without input from any upstream factors.

Autocatalytic Propagation of Tau Aggregation
Early Tau aggregates first accumulate in the cell as particulate Tau complexes (oligomers). Digestion of the aggregated Tau by proteases leaves intact a core of Tau proteins truncated in the vicinity of His-297 and at Glu-391 at the C-terminus. This forms the proteolytically stable footprint of the Tau-Tau binding domain which is able to capture normal full-length Tau protein with high affinity. Further digestion of the newly bound Tau molecule simply reproduces the proteolytically stable unit, which is able in turn to capture a further Tau molecule, and so on. Thus the process is self-propagating and self sustaining. This molecular mechanism of Tau aggregation and production of the characteristic stable core of truncated Tau found in the PHFs was elucidated experimentally by the Wischik team.