Exosomes in the Pathology of Neurodegenerative Diseases

Abstract

More than 30 years ago, two unexpected findings were discovered that challenged conventional thinking in biology. The first was the identification of a misfolded protein with transmissible properties associated with a group of neurodegenerative diseases known as transmissible spongiform encephalopathies. The second was the discovery of a new pathway used for the extracellular release of biomolecules, including extracellular vesicles called exosomes. Two decades later, the convergence of these pathways was shown when exosomes were found to play a significant role in both the transmission and propagation of protein aggregates in disease. Recent research has now revealed that the majority of proteins involved in neurodegenerative diseases are transported in exosomes, and that external stresses due to age-related impairment of protein quality control mechanisms can promote the transcellular flux of these proteins in exosomes. Significantly, exosomes provide an environment that can induce the conformational conversion of native proteins into aggregates that can be transmitted to otherwise aggregate-free cells in the brain. Here we review the current roles of exosomes in the pathology of neurodegenerative diseases.

Keywords: Alzheimer disease; Parkinson disease; exosomes; extracellular vesicles; prion; prion disease.

FIGURE 1.

Schematic depicting the pathways involved in the biogenesis of exosomes containing proteins associated with neurodegenerative diseases. A, the prion protein (PrP^c) is found on the cell surface anchored by a glycosylphosphatidylinositol (GPI) linker to lipid rafts. PrP^c can be internalized via early endosomes, and through a ceramide-dependent process (99), it can enter MVBs. MVB fusion with the cell surface results in the release of PrP^c in exosomes. B, α-synuclein is a cytoplasmic protein that can be found on early endosomes. Through a process involving ceramide, tetraspanins, or endosomal sorting complexes required for transport (ESCRT) components, α-synuclein is directed into MVBs. Both PARK9 (51, 52) and Rab11 (48) have been shown to promote the exosomal release of α-synuclein. C, APP is a cell surface transmembrane protein that can be processed by a number of proteases. APP is found on early endosomes, where it can be cleaved by secretases (71) to form secreted APPβ (sAPPβ), Aβ, and APP intracellular domain (AICD). The AICD fragment can traffic to the nucleus, whereas Aβ can be trafficked into MVBs through a process involving ceramide, tetraspanins, or ESCRT components. Fusion of the MVB with the plasma membrane results in the subsequent release of exosomes containing Aβ from the cell. Exosome-independent pathways for Aβ release can result in extracellular Aβ that can be sequestered by exosomes, which can then be degraded by microglia (73).