Dataset Information

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective.

ABSTRACT: Extracellular vesicles (EVs) are double membrane structures released by presumably all cell types that transport and deliver lipids, proteins, and genetic material to near or distant recipient cells, thereby affecting their phenotype. The basic knowledge of their functions in healthy and diseased brain is still murky and many questions about their biology are unsolved. In neurological diseases, EVs are regarded as attractive biomarkers and as therapeutic tools due to their ability to cross the blood-brain barrier (BBB). EVs have been successfully isolated from conditioned media of primary brain cells and cerebrospinal fluid (CSF), but protocols allowing for the direct study of pathophysiological events mediated or influenced by EVs isolated from brain have only recently been published. This review aims to give a brief overview of the current knowledge of EVs' functions in the central nervous system (CNS) and the current protocols to isolate brain-derived EVs (BDEVs) used in different publications. By comparing the proteomic analysis of some of these publications, we also assess the influence of the isolation method on the protein content of BDEVs.

SUBMITTER: Brenna S

PROVIDER: S-EPMC7866382 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective.

Brenna Santra S Krisp Christoph C Altmeppen Hermann Clemens HC Magnus Tim T Puig Berta B

International journal of molecular sciences 20210129 3

Extracellular vesicles (EVs) are double membrane structures released by presumably all cell types that transport and deliver lipids, proteins, and genetic material to near or distant recipient cells, thereby affecting their phenotype. The basic knowledge of their functions in healthy and diseased brain is still murky and many questions about their biology are unsolved. In neurological diseases, EVs are regarded as attractive biomarkers and as therapeutic tools due to their ability to cross the b ...[more]

PMID: 33573018

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Project description:Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer's disease, prodromal Alzheimer's disease, and non-demented control cases. Alzheimer's disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer's disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer's disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer's disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer's disease or prodromal Alzheimer's disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer's disease donor showed little tau pathology. Furthermore, Alzheimer's disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.

Project description:Human breast milk (HM) contains multiple bioactive substances determining its impact on children's health. Extracellular vesicles (EVs) are a heterogeneous group of secreted nanoparticles that are present in HM and may be partially responsible for its beneficial effects. The precise roles and content of EVs in HM remain largely unknown. To examine this, we performed a short narrative review on the literature focusing on HM EVs to contextualize the available data, followed by a scoping review of MEDLINE and Embase databases. We identified 424 nonduplicate citations with 19 original studies included. In this perspective, we summarize the evidence around HM EVs, highlight some theoretical considerations based on existing evidence, and provide an overview of some challenges associated with the complexity and heterogeneity of EV research. We consider how the existing data from HM studies conform to the minimal information for studies of EVs (MISEV) guidelines. Across the studies a variety of research methods were utilized involving both bench-based and translational methods, and a range of different EV contents were examined including RNA, proteins, and glycopeptides. We observed a variety of health outcomes in these studies, including allergy and atopy, necrotizing enterocolitis, and HIV. While some promising results have been demonstrated, the heterogeneity in outcomes of interest, methodological limitations, and relatively small number of studies in the field make comparison between studies or further translational work problematic. To date, no studies have examined normative values of HM EVs in a large, diverse population or with respect to potentially important influencing factors such as timing (hind- vs. foremilk), stage (colostrum vs. mature milk), and infant age (preterm vs. term), which makes extrapolation from bench or "basic" research impossible. Future research should focus on addressing the current inadequacies in the literature and utilize MISEV guidelines to inform study design.

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Dataset Information

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective.

Publications

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective.

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