Figure 2.

Intercellular transmission pathways in prionoid NDs. (A) Prionoid aggregates and oligomers are released into the extracellular space through exocytosis. This can occur in normal cells, but may be accelerated during pathology. (B) Cell death releases aggregates and oligomers developing within the affected neuron. Some of these are capable of persisting in the extracellular space. (C) Microglia phagocytose extracellular aggregates and oligomers. Many pathological processes weaken enzymatic degradation processes, allowing engulfed prionoid material to persist. Some prionoids may be released, either in vesicles or following death of the microglia, facilitating infection of neighboring cells. (D) Extracellular aggregates and oligomers can be taken into healthy neurons by unconfirmed processes. These include endocytosis, micropinocytosis and protein-mediated uptake. (E) Prionoid material can be transmitted directly across synapses. Alternatively, tunneling nanotubes may facilitate direct transmission between neurons. (F) Prionoid material can be internalized by astrocytes, possibly at the synapse or through tunneling nanotubules. Aggregation can progress within the astrocytes, or prionoid material can be transferred to healthy neurons through tunneling nanotubes. (G) Once prionoid material has entered a healthy neuron, it can seed pathological aggregation. Aggregates may seed conformational changes in natively conformed proteins, while oligomers may either accelerate the growth of seeded aggregates or infect functional amyloid aggregates.