Tau Spreading Mechanisms; Implications for Dysfunctional Tauopathies

Tauopathies comprise a group of progressive age-associated neurodegenerative diseases where tau protein deposits are found as the predominant pathological signature (primary tauopathies) or in combination with the presence of other toxic aggregates (secondary tauopathies). In recent years, emerging evidence suggests that abnormal tau accumulation is mediated through spreading of seeds of the protein from cell to cell, favouring the hypothesis of a prion-like transmission of tau to explain the propagation of the pathology. This would also support the concept that the pathology initiates in a very small part of the brain before becoming symptomatic and spreads across the brain over time. To date, many key questions still remain unclear, such as the nature of the tau species involved in the spreading, the precise seeding/template and uptaking mechanisms or the selectivity explaining why certain neurons are affected and some others are not. A better understanding of the tau spreading machinery will contribute to the development of new therapeutic approaches focused on halting the abnormal propagation, offering also new perspectives for early diagnosis and preventive therapies. In this review, we will cover the most recent advances in tau spreading mechanisms as well as the implications of these findings for dysfunctional tauopathies.