Roles, Functions, and Pathological Implications of Exosomes in the Central Nervous System

Abstract

Exosomes are a subset of extracellular vesicles (EVs) secreted by nearly all cell types and have emerged as a novel mechanism for intercellular communication within the central nervous system (CNS). These vesicles facilitate the transport of proteins, nucleic acids, lipids, and metabolites between neurons and glial cells, playing a pivotal role in CNS development and the maintenance of homeostasis. Current evidence indicates that exosomes from CNS cells may function as either inhibitors or enhancers in the onset and progression of neurological disorders. Furthermore, exosomes have been found to transport disease-related molecules across the blood-brain barrier, enabling their detection in peripheral blood. This distinctive property positions exosomes as promising diagnostic biomarkers for neurological conditions. Additionally, a growing body of research suggests that exosomes derived from mesenchymal stem cells exhibit reparative effects in the context of neurological disorders. This review provides a concise overview of the functions of exosomes in both physiological and pathological states, with particular emphasis on their emerging roles as potential diagnostic biomarkers and therapeutic agents in the treatment of neurological diseases.

Keywords: blood–brain barrier; exosomes; extracellular vesicles (EVs); neurodegenerative diseases; peripheral–brain axis; therapeutic delivery.

Figure 1

The typical process of exosome nomenclature, classification, biogenesis, secretion, and transfer from donor cells to recipient cells, as well as the structural characteristics of exosomes, is illustrated. Early endosomes initially form intraluminal vesicles (ILVs), which later mature into multivesicular bodies (MVBs). These MVBs then release exosomes into the extracellular space. Exosomes have a bilayer membrane structure containing functional proteins, nucleic acids, and lipids. Some of these components are transferred to recipient cells, where they regulate gene expression and cell function. Reprinted/adapted from ref. [19].

Figure 2

The biosynthesis, secretion, cellular uptake, and molecular composition of exosomes are outlined. Exosome biosynthesis starts with an endosomic pathway. The cytoplasmic membrane invaginates to create early sorting endosomes (ESEs), which mature into late sorting endosomes (LSEs). The membrane of LSEs further invaginates, forming multivesicular bodies (MVBs) that contain numerous intraluminal vesicles (ILVs). MVBs can either fuse with the plasma membrane to release ILVs as exosomes or fuse with lysosomes for degradation. Exosomes deliver specific proteins, nucleic acids, lipids, and metabolites to recipient cells through endocytosis, receptor–ligand interactions, and direct membrane fusion. Reprinted/adapted from ref. [29].

Figure 3

There are three primary types of extracellular vesicles: exosomes, microvesicles, and apoptotic bodies. Each type differs in size, biogenesis, and physiological function. Extracellular vesicles can be classified into three subtypes based on their size and biogenesis: apoptotic bodies (1000–5000 nm), which are formed during apoptosis; microvesicles (50–1000 nm); and exosomes (30–150 nm). It is important to note that, in addition to being directly produced from a cell via the endocytic pathway, exosomes can also be derived from apoptotic bodies. MVB refers to a multivesicular body. Reprinted/adapted from ref. [30].

Figure 4

Functions of exosomes as mediators of intercellular communication in both physiological and pathological contexts. Under both physiological and pathological conditions, cells can deliver substances and exchange information in multiple directions through exosomes. The following substances are commonly associated with exosome content: nGDF (nervous growth/differentiation factor), AEA (N-arachidonoylethanolamine), PLP (proteolipid protein), CNP (2′3′-cyclic-nucleotide-phosphodiesterase), PrP (prion protein), Aβ (amyloid β), IDE (insulin-degrading enzyme), and SOD1 (mutant superoxide dismutase). Reprinted/adapted from ref. [29].

Figure 5

Possible exosomal biomarkers for diagnosing neurodegenerative disorders. Exosomes derived from various brain and peripheral cells may carry disease-specific proteins, nucleic acids, and lipids, which can serve as biomarkers for the early detection and monitoring of neurodegenerative diseases (Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis). Their presence and composition in biological fluids, such as blood and cerebrospinal fluid, offer promising avenues for non-invasive diagnostic approaches.

Figure 6

An illustration depicting the potential therapeutic applications of exosomes derived from stem cells in the treatment of neurodegenerative diseases. Exosomes, secreted by stem cells, carry bioactive molecules that can modulate cellular function. These exosomes can cross the blood–brain barrier, delivering therapeutic cargo to target cells in the brain, and potentially promoting neuroprotection and regeneration in conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis (ALS).

Figure 7

Exosomes as an innovative diagnostic tool for CNS disorders. Exosomes can be released by nearly all cell types. Exosomes released by brain cells can cross the BBB and can be detected in the bloodstream. Similarly, endothelial and peripheral cells also secrete exosomes into the circulation. These exosomes can be isolated from blood samples and used for detecting various proteins and nucleic acids. Additionally, exosomal membrane markers may be used to identify the cellular origin of the exosomes. Reprinted/adapted from ref. [154].