Ectosomes: A New Mechanism for Non-Exosomal Secretion of Tau Protein

Abstract

Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.

FRMD4A–cytohesin signaling modulates the cellular release of tau

“…2J). Ceramide regulates exocytosis Rohrbough et al, 2004) and exosomal secretion (Trajkovic et al, 2008), and tau might be secreted in association with small vesicles such as exosomes and other microvesicles (Dujardin et al, 2014). GW4869, an inhibitor of ceramide generation by neutral sphingomyelinase (nSMase), reduced tauGLuc1/2 reporter secretion from HEK293T cells by 32% (Fig.…”

Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research

“…Studies also showed differences in propagation (brain areas affected, distance of spreading) after injection of recombinant tau [87,103,104] or native forms [105,107]. Interestingly, tau from human tauopathies brain extracts induced tau pathology mimicking the parent neurodegenerative diseases (Table 2).…”

“…Tau is constitutively released from neurons under physiological conditions [71,[76][77][78][79][80][81][82][83][84][85][86][87][88]. The secretion is multifaceted, involving diverse intracellular components such as autophagosomes, Golgi, endosomes, ectosomes, lysosomes, microsomes and endoplasmic reticulum [89].…”

“…The sizes of tau fibrils or aggregates also play a crucial role in the process of active endocytosis. Aggregated full-length tau or truncated tau forms are readily endocytosed by neuronal and non-neuronal cells; tau monomers, long fibrils or filaments are not [78,81,87]. Put together, the ability to seed, induce aggregation and propagate tau pathology in specific cells and cell compartments depends on tau conformation, its post-translational modification/s and size and involves a complex of known and unknown secretory and uptake mechanisms.…”

“…Various forms of tau protein like fibrils [87,103,104], filaments [28,72,105,106] and oligomers [27] or monomers [107,108] display different seeding properties despite the difference in the origin of the seeding tau protein. Studies also showed differences in propagation (brain areas affected, distance of spreading) after injection of recombinant tau [87,103,104] or native forms [105,107].…”