Extracellular Vesicles Taken up by Astrocytes

Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells. Among them, astrocytes are the most abundant glial cells in the mammalian brain and play a wide range of roles, from structural maintenance of the brain to regulation of neurotransmission. Furthermore, since astrocytes can take up EVs, it is possible that EVs originating from inside and outside the brain affect astrocyte function, which in turn affects brain function. However, it has not been fully clarified whether the specific targeting mechanism of EVs to astrocytes as recipient cells exists. In recent years, EVs have attracted attention as a cell-targeted therapeutic approach in various organs, and elucidation of the targeting mechanism of EVs to astrocytes may pave the way for new therapies for brain diseases. In this review, we focus on EVs in the brain that affect astrocyte function and discuss the targeting mechanism of EVs to astrocytes.

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Ganglioside GM1 Targets Astrocytes to Stimulate Cerebral Energy Metabolism

Frontiers in Pharmacology ◽

10.3389/fphar.2021.653842 ◽

2021 ◽

Vol 12 ◽

Author(s):

Charles Finsterwald ◽

Sara Dias ◽

Pierre J. Magistretti ◽

Sylvain Lengacher

Keyword(s):

Molecular Mechanisms ◽

Neuroprotective Effect ◽

Brain Diseases ◽

Mitochondrial Activity ◽

Ganglioside Gm1 ◽

Neuroprotective Effects ◽

Wide Range ◽

Cord Injury ◽

Clinical Benefits ◽

The Brain

Gangliosides are major constituents of the plasma membrane and are known to promote a number of physiological actions in the brain, including synaptic plasticity and neuroprotection. In particular, the ganglioside GM1 was found to have a wide range of preclinical and clinical benefits in brain diseases such as spinal cord injury, Huntington’s disease and Parkinson’s disease. However, little is known about the underlying cellular and molecular mechanisms of GM1 in the brain. In the present study, we show that GM1 exerts its actions through the promotion of glycolysis in astrocytes, which leads to glucose uptake and lactate release by these cells. In astrocytes, GM1 stimulates the expression of several genes involved in the regulation of glucose metabolism. GM1 also enhances neuronal mitochondrial activity and triggers the expression of neuroprotection genes when neurons are cultured in the presence of astrocytes. Finally, GM1 leads to a neuroprotective effect in astrocyte-neuron co-culture. Together, these data identify a previously unrecognized mechanism mediated by astrocytes by which GM1 exerts its metabolic and neuroprotective effects.

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Pathological potential of astroglia

Physiological Research ◽

10.33549/physiolres.931604 ◽

2008 ◽

pp. S101-S110

Author(s):

A Chvátal ◽

M Anděrová ◽

H Neprašová ◽

I Prajerová ◽

J Benešová ◽

...

Keyword(s):

Glial Cells ◽

Brain Parenchyma ◽

Brain Diseases ◽

Brain Pathology ◽

Pathological Conditions ◽

Recent Developments ◽

Neurological Defect ◽

Del Rio ◽

The Brain ◽

Brain Homeostasis

The pathological potential of glial cells was recognized already by Rudolf Virchow, Santiago Ramon y Cajal and Pio Del Rio-Ortega. Many functions and roles performed by astroglia in the healthy brain determine their involvement in brain diseases; as indeed any kind of brain insult does affect astrocytes, and their performance in pathological conditions, to a very large extent, determines the survival of the brain parenchyma, the degree of damage and neurological defect. Astrocytes being in general responsible for overall brain homeostasis are involved in virtually every form of brain pathology. Here we provide an overview of recent developments in identifying the role and mechanisms of the pathological potential of astroglia.

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Extracellular vesicles (exosomes and ectosomes) play key roles in the pathology of brain diseases

Molecular Biomedicine ◽

10.1186/s43556-021-00040-5 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Jacopo Meldolesi

Keyword(s):

Multiple Sclerosis ◽

Extracellular Vesicles ◽

Brain Diseases ◽

Target Cells ◽

Surface Binding ◽

Cells Of Origin ◽

Relapsing Remitting ◽

And Function ◽

The Brain

AbstractLast century, neurons and glial cells were mostly believed to play distinct functions, relevant for the brain. Progressively, however, it became clear that neurons, astrocytes and microglia co-operate intensely with each other by release/binding of signaling factors, direct surface binding and generation/release of extracellular vesicles, the exosomes and ectosomes, called together vesicles in this abstract. The present review is focused on these vesicles, fundamental in various brain diseases. Their properties are extraordinary. The specificity of their membrane governs their fusion with distinct target cells, variable depending on the state and specificity of their cells of origin and target. Result of vesicle fusion is the discharge of their cargos into the cytoplasm of target cells. Cargos are composed of critical molecules, from proteins (various nature and function) to nucleotides (especially miRNAs), playing critical roles in immune and neurodegenerative diseases. Among immune diseases is multiple sclerosis, affected by extensive dysregulation of co-trafficking neural and glial vesicles, with distinct miRNAs inducing severe or reducing effects. The vesicle-dependent differences between progressive and relapsing-remitting forms of the disease are relevant for clinical developments. In Alzheimer’s disease the vesicles can affect the brain by changing their generation and inducing co-release of effective proteins, such Aβ and tau, from neurons and astrocytes. Specific miRNAs can delay the long-term development of the disease. Upon their traffic through the blood-brainbarrier, vesicles of various origin reach fluids where they are essential for the identification of biomarkers, important for diagnostic and therapeutic innovations, critical for the future of many brain patients.

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Two peptides targeting endothelial receptors are internalized into murine brain endothelial cells

PLoS ONE ◽

10.1371/journal.pone.0249686 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249686

Author(s):

Diána Hudecz ◽

Sara Björk Sigurdardóttir ◽

Sarah Christine Christensen ◽

Casper Hempel ◽

Andrew J. Urquhart ◽

...

Keyword(s):

Endothelial Cells ◽

Transferrin Receptor ◽

Vesicular Transport ◽

Brain Diseases ◽

Brain Endothelial Cells ◽

Binding Studies ◽

Wide Range ◽

Murine Brain ◽

The Brain

The blood-brain barrier (BBB) is one of the main obstacles for therapies targeting brain diseases. Most macromolecules fail to pass the tight BBB, formed by brain endothelial cells interlinked by tight junctions. A wide range of small, lipid-soluble molecules can enter the brain parenchyma via diffusion, whereas macromolecules have to transcytose via vesicular transport. Vesicular transport can thus be utilized as a strategy to deliver brain therapies. By conjugating BBB targeting antibodies and peptides to therapeutic molecules or nanoparticles, it is possible to increase uptake into the brain. Previously, the synthetic peptide GYR and a peptide derived from melanotransferrin (MTfp) have been suggested as candidates for mediating transcytosis in brain endothelial cells (BECs). Here we study uptake, intracellular trafficking, and translocation of these two peptides in BECs. The peptides were synthesized, and binding studies to purified endocytic receptors were performed using surface plasmon resonance. Furthermore, the peptides were conjugated to a fluorophore allowing for live-cell imaging studies of their uptake into murine brain endothelial cells. Both peptides bound to low-density lipoprotein receptor-related protein 1 (LRP-1) and the human transferrin receptor, while lower affinity was observed against the murine transferrin receptor. The MTfp showed a higher binding affinity to all receptors when compared to the GYR peptide. The peptides were internalized by the bEnd.3 mouse endothelial cells within 30 min of incubation and frequently co-localized with endo-lysosomal vesicles. Moreover, our in vitro Transwell translocation experiments confirmed that GYR was able to cross the murine barrier and indicated the successful translocation of MTfp. Thus, despite binding to endocytic receptors with different affinities, both peptides are able to transcytose across the murine BECs.

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Alzheimer and vascular brain disease: Senile dementia

Dementia & Neuropsychologia ◽

10.1590/1980-57642015dn92000013 ◽

2015 ◽

Vol 9 (2) ◽

pp. 184-188 ◽

Cited By ~ 2

Author(s):

Eliasz Engelhardt ◽

Lea T. Grinberg

Keyword(s):

Senile Dementia ◽

Vascular Cognitive Impairment ◽

Brain Disease ◽

Brain Diseases ◽

Heterogeneous Condition ◽

Disease Subtype ◽

Wide Range ◽

Alois Alzheimer ◽

Short Time ◽

The Brain

Alois Alzheimer is best known for his description of a novel disease, subsequently named after him. However, his wide range of interests also included vascular brain diseases. He described Senile dementia, a highly heterogeneous condition, and was able not only to distinguish it from syphilitic brain disease, but also to discriminate two clinicopathological subtypes, that may be labeled a "arteriosclerotic subtype", comparable to the present clinicopathological continuum of "Vascular cognitive impairment", and another as a "neurodegenerative subtype", characterized by primary [cortical] ganglion cell [nerve cells] degeneration, possibly foreshadowing a peculiar presenile disease that he was to describe some years later and would carry his name. He also considered the possibility of a senile presentation of this disease subtype, which was described by Oskar Fischer a short time later. Considering the clinicopathological overlapping features of the "arteriosclerotic subtype" of Senile dementia with Arteriosclerotic atrophy of the brain, it might be possible to consider that both represent a single condition.

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Glia-Derived Extracellular Vesicles in Parkinson’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm9061941 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1941 ◽

Cited By ~ 3

Author(s):

Bianca Marchetti ◽

Loredana Leggio ◽

Francesca L’Episcopo ◽

Silvia Vivarelli ◽

Cataldo Tirolo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Extracellular Vesicles ◽

Glial Cells ◽

Donor Cell ◽

Substantia Nigra Pars Compacta ◽

Special Focus ◽

Wide Range ◽

Messenger Molecules ◽

New Biomarkers

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.

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Bayes-Optimal Chemotaxis

Neural Computation ◽

10.1162/neco_a_00075 ◽

2011 ◽

Vol 23 (2) ◽

pp. 336-373 ◽

Cited By ~ 17

Author(s):

Duncan Mortimer ◽

Peter Dayan ◽

Kevin Burrage ◽

Geoffrey J. Goodhill

Keyword(s):

System Development ◽

Sensory Information ◽

Nervous System Development ◽

Two Dimensions ◽

Physical Constraints ◽

Wide Range ◽

A Cell ◽

Varying Environments ◽

The Brain ◽

Fundamental Physical

Chemotaxis plays a crucial role in many biological processes, including nervous system development. However, fundamental physical constraints limit the ability of a small sensing device such as a cell or growth cone to detect an external chemical gradient. One of these is the stochastic nature of receptor binding, leading to a constantly fluctuating binding pattern across the cell's array of receptors. This is analogous to the uncertainty in sensory information often encountered by the brain at the systems level. Here we derive analytically the Bayes-optimal strategy for combining information from a spatial array of receptors in both one and two dimensions to determine gradient direction. We also show how information from more than one receptor species can be optimally integrated, derive the gradient shapes that are optimal for guiding cells or growth cones over the longest possible distances, and illustrate that polarized cell behavior might arise as an adaptation to slowly varying environments. Together our results provide closed-form predictions for variations in chemotactic performance over a wide range of gradient conditions.

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Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrPScSpecies

Journal of Virology ◽

10.1128/jvi.02142-15 ◽

2015 ◽

Vol 89 (24) ◽

pp. 12418-12426 ◽

Cited By ~ 22

Author(s):

Charles E. Mays ◽

Jacques van der Merwe ◽

Chae Kim ◽

Tracy Haldiman ◽

Debbie McKenzie ◽

...

Keyword(s):

Prion Proteins ◽

Surface Protein ◽

Clinical Disease ◽

Brain Diseases ◽

Disease Symptoms ◽

Symptomatic Disease ◽

A Cell ◽

Biophysical Techniques ◽

The Brain ◽

Oligomeric Forms

ABSTRACTIn lethal prion neurodegenerative diseases, misfolded prion proteins (PrPSc) replicate by redirecting the folding of the cellular prion glycoprotein (PrPC). Infections of different durations can have a subclinical phase with constant levels of infectious particles, but the mechanisms underlying this plateau and a subsequent exit to overt clinical disease are unknown. Using tandem biophysical techniques, we show that attenuated accumulation of infectious particles in presymptomatic disease is preceded by a progressive fall in PrPClevel, which constricts replication rate and thereby causes the plateau effect. Furthermore, disease symptoms occurred at the threshold associated with increasing levels of small, relatively less protease-resistant oligomeric prion particles (oPrPSc). Although a hypothetical lethal isoform of PrP cannot be excluded, our data argue that diminishing residual PrPClevels and continuously increasing levels of oPrPScare crucial determinants in the transition from presymptomatic to symptomatic prion disease.IMPORTANCEPrions are infectious agents that cause lethal brain diseases; they arise from misfolding of a cell surface protein, PrPCto a form called PrPSc. Prion infections can have long latencies even though there is no protective immune response. Accumulation of infectious prion particles has been suggested to always reach the same plateau in the brain during latent periods, with clinical disease only occurring when hypothetical toxic forms (called PrPLor TPrP) begin to accumulate. We show here that infectivity plateaus arise because PrPCprecursor levels become downregulated and that the duration of latent periods can be accounted for by the level of residual PrPC, which transduces a toxic effect, along with the amount of oligomeric forms of PrPSc.

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Effect of Peptide PV on the Ionic Permeability of Lipid Bilayer Membranes

The Journal of General Physiology ◽

10.1085/jgp.63.4.492 ◽

1974 ◽

Vol 63 (4) ◽

pp. 492-508 ◽

Cited By ~ 20

Author(s):

H. P. Ting-Beall ◽

M. T. Tosteson ◽

B. F. Gisin ◽

D. C. Tosteson

Keyword(s):

Lipid Bilayers ◽

Membrane Conductance ◽

Equilibrium Potential ◽

Lipid Bilayer Membranes ◽

Bilayer Membranes ◽

Membrane Surfaces ◽

Zero Current ◽

Wide Range ◽

Current Flows ◽

Calculated Equilibrium

This paper reports the effects of peptide PV (primary structure: cyclo-(D-val-L-pro-L-val-D-pro)δ) on the electrical properties of sheep red cell lipid bilayers. The membrane conductance (Gm) induced by PV in either Na+ or K+ medium is proportional to the concentration of PV in the aqueous phase. The PV concentration required to produce a comparable increase in Gm in K+ medium is about 104 times greater than for its analogue, valinomycin (val). Although the selectivity sequence for PV and val is similar, K+ ≳ Rb+ > Cs+ > NH4+ > TI+ > Na+ > Li+; the ratio of GGm in K+ to that in Na+ is about 10 for PV compared to > 103 for val. When equal concentrations of PV are added to both sides of a bilayer, the membrane current approaches a maximum value independent of voltage when the membrane potential exceeds 100 mV. When PV is added to only one side of a bilayer separating identical salt solutions of either Na+ or K+ salts, rectification occurs such that the positive current flows more easily away rather than toward the side containing the carrier. Under these conditions, a large, stable, zero-current potential (VVm) is also observed, with the side containing PV being negative. The magnitude of this VVm is about 90 mV and relatively independent of PV concentration when the latter is larger than 2 Times; 10–5 M. From a model which assumes that Vm equals the equilibrium potential for the PV-cation complexes (MS+) and that the reaction between PV and cations is at equilibrium on the two membrane surfaces, we compute the permeability of the membrane to free PV to be about 10–5 cm s–1, which is about 10–7 times the permeability of similar membranes to free val. This interpretation is supported by the fact that the observed values of Vm are in agreement with the calculated equilibrium potential for MS+ over a wide range of ratios of concentrations of total PV in the two bathing solutions, if the unstirred layers are taken into account in computing the MS+ concentrations at the membrane surfaces.

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Natural Polysaccharide Carriers in Brain Delivery: Challenge and Perspective

Pharmaceutics ◽

10.3390/pharmaceutics12121183 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1183

Author(s):

Manuela Curcio ◽

Giuseppe Cirillo ◽

Jourdin R. C. Rouaen ◽

Federica Saletta ◽

Fiore Pasquale Nicoletta ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Diseases ◽

Stimuli Responsive ◽

Drug Bioavailability ◽

Responsive Materials ◽

Blood Brain ◽

Wide Range ◽

Materials Used ◽

The Brain

Targeted drug delivery systems represent valuable tools to enhance the accumulation of therapeutics in the brain. Here, the presence of the blood brain barrier strongly hinders the passage of foreign substances, often limiting the effectiveness of pharmacological therapies. Among the plethora of materials used for the development of these systems, natural polysaccharides are attracting growing interest because of their biocompatibility, muco-adhesion, and chemical versatility which allow a wide range of carriers with tailored physico-chemical features to be synthetized. This review describes the state of the art in the field of targeted carriers based on natural polysaccharides over the last five years, focusing on the main targeting strategies, namely passive and active transport, stimuli-responsive materials and the administration route. In addition, in the last section, the efficacy of the reviewed carriers in each specific brain diseases is summarized and commented on in terms of enhancement of either blood brain barrier (BBB) permeation ability or drug bioavailability in the brain.

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