What is the evidence that tau pathology spreads through prion-like propagation?

Table 3 Potential modes of tau toxicity

Pathological change and Tau species implicated	Potential modes of tau toxicity	Selected References
Hyperphosphorylation (e.g. soluble monomer/dimer)	Loss Of microtubule-binding (and other) Function(s) (LOF) leading to axonal transport and synaptic defects reflected in mitochondrial clumping, Golgi disruptions and mis-sorting of synaptic proteins. Mis-localisation may also be evident causing Gain Of toxic Function (GOF). Collectively these may be responsible for neuronal dysfunction at early stages of disease. It is possible that a partial LOF is required for, and leads to an eventual GOF	[31, 32, 52, 97, 100]
Misfolding/aberrant folding and aggregation into small aggregates (e.g. sarkosyl soluble oligomers)	Neuronal dysfunction and neurodegeneration evident in some models in the absence of larger aggregates implying that smaller soluble oligomeric species responsable for these phenotypes	([53, 87])
Aggregation (into large insoluble oligomers such as granular tau oligomers and filaments including tangles)	Space-occupying lesions resulting in GOF. Toxicity debated because in some models rescue of neuronal dysfunction and degeneration evident despite persistence of larger aggregates.	([14, 31, 33, 52, 114, 122, 140])

The various pathologial changes in tau may be responsible for causing loss of normal function (LOF) or gain of toxic function (GOF). In the face of emerging novel functions of tau, there may be numerous modes of toxicity via a number of LOF mechanisms. Toxicity resulting from GOF mechanisms are more difficult to dissect but based on reports of neuronal dysfunction or neurodegeneration in the absence of large insoluble tau filaments, the tau species responsible (or not as the case may be) are begining to be understood. Recommendation: Future studies should seek to clarify terminology and consistency in ascribing modes of toxicity to tau species

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