Central nervous system-derived extracellular vesicles: the next generation of neural circulating biomarkers?

Abstract

The central nervous system (CNS) is integrated by glial and neuronal cells, and both release extracellular vesicles (EVs) that participate in CNS homeostasis. EVs could be one of the best candidates to operate as nanosized biological platforms for analysing multidimensional bioactive cargos, which are protected during systemic circulation of EVs. Having a window into the molecular level processes that are happening in the CNS could open a new avenue in CNS research. This raises a particular point of interest: can CNS-derived EVs in blood serve as circulating biomarkers that reflect the pathological status of neurological diseases? L1 cell adhesion molecule (L1CAM) is a widely reported biomarker to identify CNS-derived EVs in peripheral blood. However, it has been demonstrated that L1CAM is also expressed outside the CNS. Given that principal data related to neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease were obtained using L1CAM-positive EVs, efforts to overcome present challenges related to its specificity are required. In this sense, other surface biomarkers for CNS-derived EVs, such as glutamate aspartate transporter (GLAST) and myelin oligodendrocyte glycoprotein (MOG), among others, have started to be used. Establishing a panel of EV biomarkers to analyse CNS-derived EVs in blood could increase the specificity and sensitivity necessary for these types of studies. This review covers the main evidence related to CNS-derived EVs in cerebrospinal fluid and blood samples of patients with neurological diseases, focusing on the reported biomarkers and the technical possibilities for their isolation. EVs are emerging as a mirror of brain physiopathology, reflecting both localized and systemic changes. Therefore, when the technical hindrances for EV research and clinical applications are overcome, novel disease-specific panels of EV biomarkers would be discovered to facilitate transformation from traditional medicine to personalized medicine.

Keywords: Brain-derived EVs; Central nervous system-derived EVs; Cerebrospinal fluid EVs; Circulating biomarkers; Extracellular vesicles; Neural-derived EVs; Neurodegenerative diseases; Plasma EVs.

Fig. 1

The “yin-yang effect” of EVs in the CNS. EVs from neurons, neural stem cells and glial cells (astrocytes, oligodendrocytes and microglia) contribute to physiological processes as neuroprotection; neuronal differentiation and development; neuronal survival and viability; and synaptic function, synaptic plasticity and myelin production. On the other hand, EVs participate in pathological mechanisms such as brain cancer and neurodegenerative diseases (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer and Parkinson diseases). Other contributions of EVs in pathological conditions such as stroke, spinal cord injury, traumatic brain injury, and Huntington’s disease, have been less reported. To be noted, the experiments to prove the physiological activities of EVs were carried out using in vitro systems and some conclusions were suggested by the authors rather than experimentally proven. At the same time, contributions of EVs to CNS diseases were mainly investigated using patient samples

Fig. 2

The state-of-art of CNS-derived EVs as circulating biomarkers in blood. Thirty-one out of thirty-nine published papers that reported biomarkers in blood-EVs for MS, ALS, PD, and AD, used L1CAM to isolate putative neuron-derived EVs. Besides L1CAM, others such as GLAST in MS and AD, and MOG in MS and PD, have started to be used. Besides, dual biomarkers such as GAP43/NLGN3 are considered in AD to achieve more specificity. On the other hand, the human protein atlas database can be used to check tissue specificity and cell-type specificity. To note, all the contributions were performed using blood samples from patients with MS, ALS, PD, and AD