Glia-Derived Extracellular Vesicles in Parkinson’s Disease

Abstract

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson’s disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Notably, glial cells communicating with each other by an array of molecules, can acquire a “beneficial” or “destructive” phenotype, thereby enhancing neuronal death/vulnerability and/or exerting critical neuroprotective and neuroreparative functions, with mechanisms that are actively investigated. An important way of delivering messenger molecules within this glia-neuron cross-talk consists in the secretion of extracellular vesicles (EVs). EVs are nano-sized membranous particles able to convey a wide range of molecular cargoes in a controlled way, depending on the specific donor cell and the microenvironmental milieu. Given the dual role of glia in PD, glia-derived EVs may deliver molecules carrying various messages for the vulnerable/dysfunctional DAergic neurons. Here, we summarize the state-of-the-art of glial-neuron interactions and glia-derived EVs in PD. Also, EVs have the ability to cross the blood brain barrier (BBB), thus acting both within the CNS and outside, in the periphery. In these regards, this review discloses the emerging applications of EVs, with a special focus on glia-derived EVs as potential carriers of new biomarkers and nanotherapeutics for PD.

Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

“…As a corollary, both activated and aged glial cells secrete EVs capable of exerting both pro-and anti-inflammatory mechanisms to balance immune reactivity in the brain [51,93]. Hence, glial-derived EVs powerfully regulate the inflammatory microenvironment thanks to a panel of immunomodulatory cargoes, which may further direct the glial status to an A1/M1 or A2/M2 phenotype, with crucial consequences for neuronal survival and health, as recently reviewed in [51].…”

“…Following brain injury, astrocytes undergo gene expression changes resulting in an activated phenotype and a "reactive astrogliosis" [80]. Almost two decades ago, the concept of a dual beneficial/harmful role of reactive astrocytes and microglia in NDs, including PD [20], paved the way to further characterization of the phenotype-dependent ability of glial cells to deliver either neuroprotective or detrimental molecules for neuronal health and survival [20,22,24,51,81]. As for microglial cells [82], Liddelow and colleagues in 2017 described two different kind of reactive astrocytes, the A1 harmful phenotype and the A2 protective one [83].…”

“…On the contrary, the M2 polarized microglia are associated with the release of anti-inflammatory cytokines (e.g., IL-4 and IL-10), neurotrophic factors (e.g., BDNF and IGF-1) and extracellular matrix proteins (e.g., fibronectin) [55,57,92]. As a corollary, both activated and aged glial cells secrete EVs capable of exerting both pro-and anti-inflammatory mechanisms to balance immune reactivity in the brain [51,93]. Hence, glial-derived EVs powerfully regulate the inflammatory microenvironment thanks to a panel of immunomodulatory cargoes, which may further direct the glial status to an A1/M1 or A2/M2 phenotype, with crucial consequences for neuronal survival and health, as recently reviewed in [51].…”

“…This is potentially achievable by using lipid-based vehicles, such as EVs, which display an innate low immunogenicity and an intrinsic ability to cross biological barriers [232]. Moreover, an increasing body of evidence supports the neuroprotective/neuroregenerative potential of EVs, with specific therapeutically relevant outcomes depending on the donor cells and the microenvironmental milieu [50,51].…”

“…In NDs, EVs were initially characterized as vehicles for misfolded or dysfunctional mutant proteins, such as amyloid-beta oligomers in Alzheimer's disease (AD) [47], SOD1 in amyotrophic lateral sclerosis (ALS) [48], or α-Syn in PD [49]. In line with the dual role described for glial cells, this view was gradually challenged in the last decade by the demonstration that EVs can play relevant neuroprotective functions in several degenerative conditions (including PD), as we and others recently reviewed [50,51].…”