Tau Propagation Mechanisms: Cell Models, Animal Models, and Beyond

Clinical studies of amyloid-β-targeting therapies in Alzheimer’s disease (AD) have revealed that the treatments after disease onset have little effect on the cognition of patients. The main strategies proposed in tau-based drug discovery, are approaches to ameliorate tau-associated neuronal death. These include inhibitors of tau phosphorylation, aggregation blockers, and promoters of tau clearance. However, recently new disease models have shed light on a new proposed molecular mechanism, the tau prion hypothesis, which could be a promising therapeutic target for tauopathies.

Tauopathies feature progressive intraneuronal deposition of aggregated tau proteins. In Alzheimer’s disease, tau aggregates deposit in a stereotypical manner along anatomically connected networks from the transentorhinal cortex to neocortical areas. Along with this classical observation, intracerebral injection of brain extracts containing aggregated tau or recombinant tau seeds induces tauopathy in tau-transgenic mice and wild-type mice. The induced tau lesions propagate from the injection site to other regions in aconnectome-dependent manner. This phenomenon strongly supports the view that tau protein has the ability to transfer as “prion-like”particles from one cell to another, similar to the aggregated form of prion protein in Creutzfeldt-Jacob disease. The cell-to-cell “prion-like” transfer of misfolded tau aggregates involves release from one neuron, uptake by nearby or remote neurons and finally, seeded assembly of the misfolded host protein in recipient neurons. Extracellular release of tau could occur actively from live neurons, including through extrusion in membrane vesicles or as free tau protein, or it could occur passively as a result of its release from dead cells. Active release may be modulated by physiological cell functions, such as lysosomal exocytosis, Golgi dynamics, or stimulation of neuronal activity. Cells could internalize aggregated tau protein through an endocytotic mechanism or macropinocytosis. These internalized tau fibrils could then induce seed-dependent aggregation of endogenoustau protein.

To provide a more complete picture of tau protein propagation, this Research Topic invites contributions of studies or reviews from areas including cell culture experiments, tau protein structure, animal models, human neuropathology and establishment of fluid biomarkers associated with tau protein propagation.