Review
Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease

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Highlights

CNS EVs are heterogenous vesicles with loading of specific cargo molecules, depending on the cell type, cellular activity, and homeostatic/disease status of the CNS.

CNS EVs cargos represent relatively small quantities of molecules compared with secreted molecules, but can be highly impactful due to their concentration and targeted delivery.

CNS EVs are active mediators of neuroimmune communication via small RNAs and proteins in the healthy and diseased brain, and have both beneficial and detrimental roles.

CNS EVs participate in seeding and progression of neurodegenerative disease pathology.

The dynamics of CNS function rely upon omnidirectional communication among CNS cell types. Extracellular vesicles (EVs) have emerged as key mediators of this communication and are actively involved in response to CNS injury, mediating inflammatory response and inflammation-related neuroprotection as they display dual beneficial and detrimental roles. Neuroimmune interactions include communication between neurons and microglia, the resident macrophages within the CNS, and these interactions are a critical mediator of healthy brain functions, mounting an inflammatory response, and disease pathogenesis. This review aims to organize recent research highlighting the role of EVs in health and neurodegenerative disorders, with a specific focus on neuroimmune interactions between neurons and glia in Alzheimer’s disease.

Section snippets

CNS Cells and EVs in Health and Disease

Neurons and glial cells (see Glossary) orchestrate CNS homeostasis through multiple mechanisms of transcellular communication known as ‘neuroimmune interactions’. These interactions range from local cell-to-cell direct contact to the use of soluble factors for short and long-distance transfer of biological material. As described decades ago, EVs appear to be potent mediators of intercellular communication, and have garnered substantial attention as a fundamental component of neuroimmune

Neuroimmune Communication with EVs

The intersection of immunology and neuroscience has been receiving increasing interest in recent years, as more research reveals multiple functional connections between the immune and nervous systems. Understanding this convergence is of particular importance in the CNS, where microglia, the resident immune cells of the brain, closely interact with neurons during development and adulthood for the maintenance of brain homeostasis and innate immune response to CNS insults. Communication between

EV-Mediated Crosstalk in CNS Homeostasis

EV-mediated crosstalk between CNS cells is mediated by EV cargo content as well as direct surface contact, and occurs in an omnidirectional manner, where all cell types influence and communicate with one another. This section describes the functional role of EVs relative to CNS cell types in a homeostatic state.

EV Crosstalk in CNS Disease

Cumulative evidence over the last few decades has shed light on the role of EVs in neurodegenerative disease pathogenesis and progression. Neurodegenerative diseases are characterized by a progressive and irreversible loss of neurons, the aggregation of misfolded proteins in the brain, and widespread neuroinflammation. EVs’ contribution to disease progression has been described in AD, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), multiple sclerosis (MS), Parkinson’s disease

Concluding Remarks and Future Perspectives

The accumulated findings regarding EV biogenesis, secretion, and uptake have allowed us to better understand their role in modulating CNS function under normal and pathological conditions. EVs represent a unique mode of intercellular communication, which allows proximal and distant interactions among multiple cell types in the CNS and periphery. EVs are involved in a wide variety of homeostatic processes, including modulation of neuronal excitability, synaptic plasticity, myelination,

Acknowledgments

We would like to thank Dr Seiko Ikezu for the scientific guidance and critical editing of this manuscript. This work is funded in part by Nancy Lurie Marks Family Foundation (T.I.), Robert E. Landreth and Dona Landreth Family Foundation (T.I.), BrightFocus Foundation (A2016551S), Cure Alzheimer’s Fund, NIH R01AG054672 (T.I.), RF1AG054199 (T.I.), R56AG057469 (T.I.), and 5T32GM008541 (S.H.).

Glossary

Alzheimer’s disease (AD)
a chronic neurodegenerative disease resulting in increased decline in cognitive function over time.
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. An ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission within the CNS.
Amyloid-β peptide (Aβ)
peptides of 36–43 amino acids, which are found as accumulated plaques in the brains of patients with AD. Amyloid-β proteins are fragments of the cleaved amyloid precursor protein.

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