Abstract
Traumatic brain injury (TBI) is a heterogeneous condition, associated with diverse etiologies, clinical presentations and degrees of severity, and may result in chronic neurobehavioral sequelae. The field of TBI biomarkers is rapidly evolving to address the many facets of TBI pathology and improve its clinical management. Recent years have witnessed a marked increase in the number of publications and interest in the role of extracellular vesicles (EVs), which include exosomes, cell signaling, immune responses, and as biomarkers in a number of pathologies. Exosomes have a well-defined lipid bilayer with surface markers that reflect the cell of origin and an aqueous core that contains a variety of biological material including proteins (e.g., cytokines and growth factors) and nucleic acids (e.g., microRNAs). The presence of proteins associated with neurodegenerative changes such as amyloid-β, α-synuclein and phosphorylated tau in exosomes suggests a role in the initiation and propagation of neurological diseases. However, mechanisms of cell communication involving exosomes in the brain and their role in TBI pathology are poorly understood. Exosomes are promising TBI biomarkers as they can cross the blood-brain barrier and can be isolated from peripheral fluids, including serum, saliva, sweat, and urine. Exosomal content is protected from enzymatic degradation by exosome membranes and reflects the internal environment of their cell of origin, offering insights into tissue-specific pathological processes. Challenges in the clinical use of exosomal cargo as biomarkers include difficulty in isolating pure exosomes, variable yields of the isolation processes, quantification of vesicles, and lack of specificity of exosomal markers. Moreover, there is no consensus regarding nomenclature and characteristics of EV subtypes. In this review, we discuss current technical limitations and challenges of using exosomes and other EVs as blood-based biomarkers, highlighting their potential as diagnostic and prognostic tools in TBI.
Highlights
Traumatic brain injury (TBI) is a major cause of disability worldwide, affecting an estimated 10 million people annually, representing a growing burden to public health [1, 2]
Among Veterans without TBI, subjects with cognitive impairment (CI) had significantly elevated levels of PRPc, SYNGR3, P-T181-tau, and Aβ42, in comparison to controls without CI. These findings suggest that neuronal amyloid β (Aβ) peptides and P-tau species remain elevated for decades after TBI, may be associated with TBI-related cognitive alterations and neurodegenerative changes, and should be considered as potential therapeutic targets
Blood-based extracellular vesicles (EVs) biomarkers confer advantages when compared to free proteins and miRNAs, as EVs cross the Blood-brain barrier (BBB) and their membrane protects the cargo from degradation
Summary
Traumatic brain injury (TBI) is a major cause of disability worldwide, affecting an estimated 10 million people annually, representing a growing burden to public health [1, 2]. A study in AD patients reported higher levels of classical and alternative complement pathway proteins in ADE when compared to matched controls, suggesting the existence of signaling mechanisms involving inflammatory mediators released by activated astrocytes via EVs [150]. This approach could shed light on the roles played by distinct cell types in the body in response to a TBI as well as FIGURE 2 | (A) Use of antibodies against cell surface proteins present on exosomes allows for isolation of neuronal-, microglial-, and astrocyte-derived exosomes. When looking at neuronal biomarkers, researchers must be cautious in interpreting results when improper collection or processing measures were used
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