The microtubule-associated protein tau is mainly expressed within neurons where it performs its physiological function of microtubule stability. However, extracellular tau is found in models of tau overexpression in which neuronal degeneration and cell death is prominent. The role of extracellular tau is under discussion. Extracellular tau could interact with cell receptors resulting in cell signaling and increase intracellular calcium, a toxic event. Thus, tau, apart from its well-established intracellular functions in microtubule stabilization and axonal transport, may possess in its extracellular form, an important alternative signaling role that could contribute to the neurodegenerative process in Alzheimer’s disease (AD). This role of extracellular tau may depend on whether it is in a monomeric or aggregated form. Tau plays a critical role in the pathogenesis of AD, and prominent tau pathology is present in several related disorders collectively known as tauopathies because of these shared histopathological/biochemical features. Development of tau pathology closely associates with progressive neuronal loss and cognitive decline. In the brains of AD patients, for instance, tau pathology follows an anatomically defined pattern described by the commonly used neuropathological Braak sequential staging.
Recent studies have shown that misfolding of tau in diseased brain leads to the appearance of abnormal conformations (and aggregation) of the protein that can be taken up by surrounding neurons. Accumulation of abnormal tau could be mediated by the spreading of seeds of the protein from cell to cell, pointing to the involvement of extracellular tau species as the main agent in the neuron-to-neuron propagation of neurofibrillary pathology and progression of tau toxicity that spreads throughout different brain regions in those disorders. This idea supports the concept that pathology initiates in a very small part of the brain many years before becoming symptomatic by spreading progressively to the whole brain within 15-20 years, perhaps reminiscent of some features of the prion protein propagation mechanism.
The fact that misfolded tau can be secreted and taken up by adjacent neurons calls for the development of novel therapeutic strategies aimed at blocking the propagation of tau pathology in the brain. Preventing the initial formation of the abnormal tau seeds or decreasing the amount of extracellular tau might block the subsequent propagation of tau aggregates, thus representing future potential therapeutic strategies.
However, key questions remain open and understanding the precise molecular mechanism underlying tau propagation is crucial for the development of therapeutics. Also, the precise relationship between tau release under physiological conditions and the propagation of pathology in AD and other tauopathies remains to be determined. At a basic level, more work should be done to understand the mechanisms for tau secretion in soluble or aggregated form, for tau uptake in neurons, or to confirm a possible tau transmission through the synaptic contacts for its cell-cell propagation. Thus, more research is needed to identify disease mechanisms driving release and propagation of tau pathology and to determine the impact of extracellular tau on cognitive decline during neurodegeneration. Finally, the relationship between tau post-translational modifications such as phosphorylation, glycosylation, acetylation, and truncation, among others with the cellular mechanisms of tau release and spreading must be elucidated.
Is secretion of fragmented and full-length tau by the same mechanism?