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

Abstract

Last 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.

Keywords: Alzheimer’s disease; Astrocytes; Immunological and neurodegenerative diseases; Microglia; Multiple sclerosis; Neurons.

Fig. 1

The two types of EVs: exosomes (left) and ectosomes (right). The figure shows the two types of EVs. In terms of size the exosomes (gold content) are smaller (diameters of 50–150 nm) while the ectosomes (sky-blue content) are larger (diameter of 150–500 nm). In terms of composition the membranes of exosomes are rich in tetraspanins, a protein complex highly important for the distribution of other proteins including those trapped at the luminal surface. A lower density of tetraspanins is present in the membrane of ectosomes. A similar partial difference is true for integrins and proteoglycans. In contrast, the adhesion molecule 1 (ICAM-1), is appreciable only in the exosome membrane. The ectosome membrane is rich in other proteins: receptors, glycoproteins, metalloproteinases and others. Among the EV membrane proteins, some of the cytosol establish specific binding with surface receptors of target cells, a process necessary for the subsequent EV uptake. The lumenal cargos are similar in the two EV types. They contain many typical proteins (blue strings), some of which anchored to the EV membrane, mixed with low concentrations of cytosolic proteins. The lumena of both EVs show various types of orange sequences composed by nucleic acids, i.e. the coding mRNAs, the non-coding miRNAs and cicrRNAs and, in some cases, also DNA sequences. Reproduced with permission from Fig. 2 of Ref. 2

Fig. 2

Secretion of EVs by the cell A, their navigation in the extracellular space, and their uptake by the target cell B and a blood capillary C. Secretion is shown in the upper cell (A, gray color). Exosomes (small, red), previously accumulated within multi-vesicular bodies (MVB) of endocytic nature, are released upon the exocytosis of the latter (a) [1]. Ectosomes are secreted by a completely different process: upon their assembly and growth at the cytosolic surface of peculiar rafts continuous to the plasma membrane (b,c) they are converted into EVs released from the cell surface by pinching off and then shedding of the rafts (d). As it occurs within tissues, the EVs navigating in the extracellular space are addressed to various targets (two in this Figure). The cell to the left (B) receives EVs released from the left side of cell A. Upon their association by receptor binding to the surface of cell B, the EVs disassemble their cargos which are transferred to the cytoplasm along green short lines (e); for other EVs the process is analogous, however it occurs after their endocytic uptake and internalization (g,h). The EVs to the right are taken up into a large blood capillary lumen (C, red pink color), reached upon their transfer first across the blood-brainbarrier (not shown) and then through the junctions between endocytic cells, pointed here by arrows

Fig. 3

A neuron of the ALS disease shows alteration of variously distributed structures: from the cytoplasm, axon and synapses. Organelles of the cytoplasm include mitochondria (pink), lysosomes (green) and others; an axon includes two altered myelins (dashed lines) as well as several, variously altered presynaptic structures (red)

Fig. 4

The three types of brain cells, neurons (N), astrocytes (A) and microglia (M), together with EVs they have secreted. For each parental cell and its EVs the color is the same: black for the neuron, orange for the astrocyte, green for the microglia. The blue ring sequence covering the neuronal axon is due to a myelin sheath. The EVs are distributed in the extracelluar space. Some of them are distributed close to their cell of origin, possibly because they have been secreted recently. The EV mixture of the three colors in the space among the cells may be due to vesicles addressed to specific targets, cells and fluids (CSF, blood serum, not shown)