Specific Extracellular Vesicles, Generated and Operating at Synapses, Contribute to Neuronal Effects and Signaling.

In all cell types, small EVs, very abundant extracellular vesicles, are generated and accumulated within MVB endocytic cisternae. Upon MVB fusion and exocytosis with the plasma membrane, the EVs are released to the extracellular space. In the central nervous system, the release of neuronal EVs was believed to occur only from the surface of the body and dendrites.

Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies.

Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction of the conditions accounting for the heterogeneity of autism. The disease was discovered 75 years ago, and the present review, based on critical evaluations of the recognized ASD studies from the beginning of 1990, has been further developed by the comparative analyses of the research and clinical reports, which have grown progressively in recent years up to late 2023. The tools necessary for the identification of the ASD disease and its related clinical pathologies are genetic and epigenetic mutations affected by the specific interaction with transcription factors and chromatin remodeling processes occurring within specific complexes of brain neurons.

Role of Senescent Astrocytes in Health and Disease.

For many decades after their discovery, astrocytes, the abundant glial cells of the brain, were believed to work as a glue, supporting the structure and metabolic functions of neurons. A revolution that started over 30 years ago revealed many additional functions of these cells, including neurogenesis, gliosecretion, glutamate homeostasis, assembly and function of synapses, neuronal metabolism with energy production, and others. These properties have been confirmed, limited however, to proliferating astrocytes.

Four distinct cytoplasmic structures generate and release specific vesicles, thus opening the way to intercellular communication.

In all cells, generation and release of specific vesicles are the initial steps of back-and-forth intercellular communication. These processes are critical in normal physiology and pathophysiology. Vesicles have particular functions appropriate to their targets.

Unconventional protein secretion (UPS): role in important diseases.

Unconventional protein secretion (UPS) is the new secretion process discovered in liquid form over three decades ago. More recently, UPS has been shown to operate also in solid forms generated from four types of organelles: fractions of lysosomes and autophagy (APh) undergoing exocytosis; exosomes and ectosomes, with their extracellular vesicles (EVs). Recently many mechanisms and proteins of these solid forms have been shown to depend on UPS.

News about Structure and Function of Synapses: Health and Diseases.

During the last century, synapses have been intensely investigated as the most interesting sites of neuroscience development [...

Post-Synapses in the Brain: Role of Dendritic and Spine Structures.

Brain synapses are neuronal structures of the greatest interest. For a long time, however, the knowledge about them was variable, and interest was mostly focused on their pre-synaptic portions, especially neurotransmitter release from axon terminals. In the present review interest is focused on post-synapses, the structures receiving and converting pre-synaptic messages.

Unconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes.

In addition to conventional protein secretion, dependent on the specific cleavage of signal sequences, proteins are secreted by other processes, all together called unconventional. Among the mechanisms operative in unconventional secretion, some are based on two families of extracellular vesicle (EVs), expressed by all types of cells: the exosomes (before secretion called ILVs) and ectosomes (average diameters ∼70 and ∼250 nm). The two types of EVs have been largely characterized by extensive studies.

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development.

Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes.

News about Therapies of Alzheimer's Disease: Extracellular Vesicles from Stem Cells Exhibit Advantages Compared to Other Treatments.

Upon its discovery, Alzheimer's, the neurodegenerative disease that affects many millions of patients in the world, remained without an effective therapy. The first drugs, made available near the end of last century, induced some effects, which remained only marginal. More promising effects are now present, induced by two approaches.

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

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.

Extracellular Vesicles of Mesenchymal Stem Cells: Therapeutic Properties Discovered with Extraordinary Success.

Mesenchymal stem cells (MSCs), the cells distributed in the stromas of the body, are known for various properties including replication, the potential of various differentiations, the immune-related processes including inflammation. About two decades ago, these cells were shown to play relevant roles in the therapy of numerous diseases, dependent on their immune regulation and their release of cytokines and growth factors, with ensuing activation of favorable enzymes and processes. Such discovery induced great increase of their investigation.

News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases.

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma.

News About the Extracellular Vesicles from Mesenchymal Stem Cells: Functions, Therapy and Protection from COVID-19.

This is a Commentary of a review about extracellular vesicles of immune cells published two years ago in Clinical and Experimental Immunology, a prestigious journal of the field. The aim is to establish whether, and to what extent, results in scientific area of the review have been extended and strengthened by innovative findings of considerable interest. The analysis of the recently published results has revealed that in various areas of the review developments have occurred.

Astrocytes: News about Brain Health and Diseases.

Astrocytes, the most numerous glial cells in the brains of humans and other mammalian animals, have been studied since their discovery over 100 years ago. For many decades, however, astrocytes were believed to operate as a glue, providing only mechanical and metabolic support to adjacent neurons. Starting from a "revolution" initiated about 25 years ago, numerous astrocyte functions have been reconsidered, some previously unknown, others attributed to neurons or other cell types.

Gene Expression in the Physiology and Pathology of Neurons.

The expression of genes is the first process governing the molecular and structural specificity of the various types of cells, initiated by their transcription into the corresponding pre-mRNA [...

Alternative Splicing by NOVA Factors: From Gene Expression to Cell Physiology and Pathology.

NOVA1 and NOVA2, the two members of the NOVA family of alternative splicing factors, bind YCAY clusters of pre-mRNAs and assemble spliceosomes to induce the maintenance/removal of introns and exons, thus governing the development of mRNAs. Members of other splicing families operate analogously. Activity of NOVAs accounts for up to 700 alternative splicing events per cell, taking place both in the nucleus (co-transcription of mRNAs) and in the cytoplasm.

Alzheimer's disease: Key developments support promising perspectives for therapy.

Alzheimer's is the neurodegenerative disease affecting the largest number of patients in the world. In spite of the intense research of the last decades, progress about its knowledge and therapy was limited. In particular, various cytotoxic processes remained debated, while the few drugs approved for therapy were of only marginal relevance.

Exosomes and Ectosomes in Intercellular Communication.

Exosomes and ectosomes, two distinct types of extracellular vesicles generated by all types of cell, play key roles in intercellular communication. The formation of these vesicles depends on local microdomains assembled in endocytic membranes for exosomes and in the plasma membrane for ectosomes. These microdomains govern the accumulation of proteins and various types of RNA associated with their cytosolic surface, followed by membrane budding inward for exosome precursors and outward for ectosomes.

Neurotrophin Trk Receptors: New Targets for Cancer Therapy.

In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75 and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75, activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75 induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action.

Neurotrophin receptors in the pathogenesis, diagnosis and therapy of neurodegenerative diseases.

In the last few years, exciting properties have emerged regarding the activation, signaling, mechanisms of action, and therapeutic targeting of the two types of neurotrophin receptors: the p75 with its intracellular and extracellular peptides, the Trks, their precursors and their complexes. This review summarizes these new developments, with particular focus on neurodegenerative diseases. Based on the evolving knowledge, innovative concepts have been formulated regarding the pathogenesis of these diseases, especially the Alzheimer's and two other, the Parkinson's and Huntington's diseases.

PRRT2: from Paroxysmal Disorders to Regulation of Synaptic Function.

In the past few years, proline-rich transmembrane protein (PRRT)2 has been identified as the causative gene for several paroxysmal neurological disorders. Recently, an important role of PRRT2 in synapse development and function has emerged. Knock down of the protein strongly impairs the formation of synaptic contacts and neurotransmitter release.

Binding and Fusion of Extracellular Vesicles to the Plasma Membrane of Their Cell Targets.

Exosomes and ectosomes, extracellular vesicles of two types generated by all cells at multivesicular bodies and the plasma membrane, respectively, play critical roles in physiology and pathology. A key mechanism of their function, analogous for both types of vesicles, is the fusion of their membrane to the plasma membrane of specific target cells, followed by discharge to the cytoplasm of their luminal cargo containing proteins, RNAs, and DNA. Here we summarize the present knowledge about the interactions, binding and fusions of vesicles with the cell plasma membrane.