Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases

Abstract

Extracellular vesicles (EVs) are nano-sized membrane-enclosed particles released by cells that participate in intercellular communication through the transfer of biologic material. EVs include exosomes that are small vesicles that were initially associated with the disposal of cellular garbage; however, recent findings point toward a function as natural carriers of a wide variety of genetic material and proteins. Indeed, exosomes are vesicle mediators of intercellular communication and maintenance of cellular homeostasis. The role of exosomes in health and age-associated diseases is far from being understood, but recent evidence implicates exosomes as causative players in the spread of neurodegenerative diseases. Cells from the central nervous system (CNS) use exosomes as a strategy not only to eliminate membranes, toxic proteins, and RNA species but also to mediate short and long cell-to-cell communication as carriers of important messengers and signals. The accumulation of protein aggregates is a common pathological hallmark in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. Protein aggregates can be removed and delivered to degradation by the endo-lysosomal pathway or can be incorporated in multivesicular bodies (MVBs) that are further released to the extracellular space as exosomes. Because exosome transport damaged cellular material, this eventually contributes to the spread of pathological misfolded proteins within the brain, thus promoting the neurodegeneration process. In this review, we focus on the role of exosomes in CNS homeostasis, their possible contribution to the development of neurodegenerative diseases, the usefulness of exosome cargo as biomarkers of disease, and the potential benefits of plasma circulating CNS-derived exosomes.

Keywords: biomarkers; central nervous system; exosomes; neural-derived exosomes; neurodegenerative diseases.

FIGURE 1

Characterization of exosomes released from human neural stem cells differentiated from Huntington’s Disease iPS cells. (A) Left: Electron micrographs of exosomes released from neural stem cell membrane, scale 200 nm. Right: Exosome with a lipid bilayer membrane sizing 50 nm. (B) Nanoparticle Tracking Analysis (NTA) of exosomes with sizes ranging from 67.7 to 152.1 nm (10th; 90th percentile) cited from Lopes et al. (2020).

FIGURE 2

Exosome biogenesis, secretion, and interaction in the central nervous system. (A) Exosomes originated in the endocytic pathway as ILVs resulting in the formation of LE with multiple small vesicles termed MVBs. During this process, exosomes are loaded with proteins, lipids, and genetic material. Afterward, the MVBs can be destined for lysosomal degradation or fused with the plasma membrane and the exosomes released into the extracellular space. The exosomes have a complex composition of proteins such as ALIX, TSG101 and flotillin, Rab family, tetraspanins (e.g., CD63, CD81, and CD9), mitochondrial proteins, and others; lipids including cholesterol, sphingomyelin, glycosphingolipids, and ceramide; and nucleic acids especially RNA and also nuclear and mitochondrial DNA. (B) Exosomes can be released from NSC/NP, neurons, astrocytes, oligodendrocytes, and microglia acting in proximal or distal cells. Exosomes can be shuttled between the different neural cells modulating distinct neuronal processes such as neurogenesis, synaptic function, neuronal plasticity, and neuroinflammation. (1) In neurons, exosomes are released in response to stimulus, such as calcium influx, glutamatergic synaptic activity, and potassium-induced depolarization. (2) The exosome signaling pathways include neuron-to-neuron communication. (3) NSC can influence the microglia function, and exosomes released from glial cells exert effects on NSC. (4) Additionally, exosomes originated in astrocytes can be fundamental for the trophic support of neurons. (5) Oligodendrocytes can also shuttle to neuron exosomes containing myelin proteins and glycolytic enzymes. ILVs, intraluminal vesicles; EEs, early endosomes; MVBs, multivesicular bodies, NSC/NP, neural stem/progenitor cells.