Mechanisms of secretion and spreading of pathological tau protein

Abstract

Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-tocell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

Highly efficient intercellular spreading of protein misfolding mediated by viral ligand - receptor interactions

“…Dissemination of protein aggregates between cells can occur by secretion of membranefree naked aggregates, secretion as vesicular cargo or via direct cell-to-cell contact. As most disease-associated proteins are secreted in a membrane-free state, it is unclear how much cell-to-cell contact and EV-mediated transfer really contribute to protein aggregate spreading 10 . We reasoned that proteopathic seed transmission involving the latter two pathways is at least partially controlled at the cell entry step.…”

“…Interestingly, such proteopathic seeds not only recruit monomeric protein in the affected cell, but also in unaffected cells upon intercellular transmission, a process that likely underlies the often observed stereotypical spreading of protein misfolding in neurodegenerative diseases 1 . In fact, intercellular transmission of proteopathic seeds is regarded as a common mechanism of neurodegenerative diseases 10 .…”

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

“…In previous studies, it has been proven the seeding nature of Tau as it causes template-dependent aggregation on uptake by healthy neurons [11]. The aggregated extracellular Tau species secreted by various mechanisms have tendency to propagate the disease [41][42][43]. The use of other omega-3 fatty acids DHA, EPA has been studied for the uptake of extracellular Aβ-plaques and their clearance [14,44].…”

α- Linolenic Acid Modulates Phagocytosis of Extracellular Tau and Induces Microglial Migration

“…In previous studies, it has been proven the seeding nature of Tau as it causes template-dependent aggregation on uptake by healthy neurons [11]. The aggregated extracellular Tau species secreted by various mechanisms have tendency to propagate the disease [36][37][38]. The use of other omega-3 fatty acids DHA, EPA has been studied for the uptake of extracellular Aβ-plaques and their clearance [14,39].…”