Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target

Abstract

Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and α-synuclein, can propagate aggregates between cells in a prion-like manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.

Keywords: Aggregate Propagation; Alpha-Synuclein (a-Synuclein); Chemoprevention; Neurodegenerative Disease; Prion; Tau Protein (Tau); Therapy.

FIGURE 1.

Cellular mechanisms of transcellular propagation. 1, proteopathic seeds accumulate within neurons where they can be released freely, or 2, in association with vesicles, such as exosomes. 3, extracellular proteopathic seeds such as Tau and α-synuclein can bind cell surface HSPGs. 4, binding of aggregated species stimulates macropinocytosis, an actin-driven uptake process that results in the internalization of seeds. 5, through unknown mechanisms, proteopathic seeds escape the lumen of the macropinosome where they can convert cognate monomer into aggregates via templated conformational change. 6, in some instances, seeds may directly translocate across the plasma membrane. 7, the process of transcellular propagation can be inhibited either by antibodies that can target extracellular species or by heparin mimetics that sequester proteopathic seeds away from their heparan sulfate receptor sites.