Alzheimer's disease brain‐derived extracellular vesicles reveal altered synapse‐related proteome and induce cognitive impairment in mice DOI Creative Commons
Victor Bodart‐Santos,

Lisandra S. Pinheiro,

Almir Jordão da Silva‐Junior

et al.

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(12), P. 5418 - 5436

Published: May 19, 2023

Abstract INTRODUCTION Extracellular vesicles (EVs) have been implicated in the spread of neuropathology Alzheimer's disease (AD), but their involvement behavioral outcomes linked to AD remains be determined. METHODS EVs isolated from post mortem brain tissue control, AD, or frontotemporal dementia (FTD) donors, as well APP/PS1 mice, were injected into hippocampi wild‐type (WT) a humanized Tau mouse model (hTau/mTauKO). Memory tests carried out. Differentially expressed proteins assessed by proteomics. RESULTS Both AD‐EVs and APP/PS1‐EVs trigger memory impairment WT mice. We further demonstrate that FTD‐EVs carry protein, present altered protein composition associated with synapse regulation transmission, hTau/mTauKO DISCUSSION Results negative impacts on mice suggest that, addition spreading pathology, may contribute FTD. Highlights Aβ was detected enriched PSP FTD tissue. AD‐derived induce cognitive AD‐ FTD‐derived Proteomics findings associate dysregulation tauopathies.

Language: Английский

Exosomes based strategies for brain drug delivery DOI
Fawad Ur Rehman, Yang Liu, Meng Zheng

et al.

Biomaterials, Journal Year: 2022, Volume and Issue: 293, P. 121949 - 121949

Published: Dec. 8, 2022

Language: Английский

Citations

120
Human neural cell type‐specific extracellular vesicle proteome defines disease‐related molecules associated with activated astrocytes in Alzheimer's disease brain DOI Creative Commons
Yang You, Satoshi Muraoka,

Mark P. Jedrychowski

et al.

Journal of Extracellular Vesicles, Journal Year: 2022, Volume and Issue: 11(1)

Published: Jan. 1, 2022

In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced pluripotent stem cell-derived neural cell types (excitatory neurons, astrocytes, microglia-like cells, oligodendrocyte-like cells). Novel type-specific EV protein markers then identified for excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), cells (ITGAM, LCP1), (LAMP2, FTH1), as well 16 pan-EV marker candidates, including integrins annexins. To further demonstrate how cell-type-specific may be Alzheimer's (AD), we performed co-expression network analysis conducted type assessments proteomes brain-derived control, mild cognitive impairment, AD cases. A module enriched astrocyte-specific was most significantly associated with pathology suggesting an important role The hub this module, integrin-β1 (ITGB1), found to elevated total brain β-amyloid tau load independent cohorts. Thus, our study provides a featured framework rich resource future analyses functions diseases manner.

Language: Английский

Citations

95
Future of Digital Assays to Resolve Clinical Heterogeneity of Single Extracellular Vesicles DOI
Renee‐Tyler T. Morales, Jina Ko

ACS Nano, Journal Year: 2022, Volume and Issue: 16(8), P. 11619 - 11645

Published: July 29, 2022

Extracellular vesicles (EVs) are complex lipid membrane vehicles with variable expressions of molecular cargo, composed diverse subpopulations that participate in the intercellular signaling biological responses disease. EV-based liquid biopsies demonstrate invaluable clinical potential for overhauling current practices disease management. Yet, EV heterogeneity is a major needle-in-a-haystack challenge to translate their use into practice. In this review, existing digital assays will be discussed analyze EVs at single vesicle resolution, and future opportunities optimize throughput, multiplexing, sensitivity highlighted. Furthermore, review outline challenges impact translation technologies diagnostics treatment monitoring.

Language: Английский

Citations

83
Biomarkers for parkinsonian disorders in CNS-originating EVs: promise and challenges DOI Creative Commons
Suman Dutta, Simon Hornung,

Hash Brown Taha

et al.

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 145(5), P. 515 - 540

Published: April 4, 2023

Abstract Extracellular vesicles (EVs), including exosomes, microvesicles, and oncosomes, are nano-sized particles enclosed by a lipid bilayer. EVs released virtually all eukaryotic cells have been shown to contribute intercellular communication transporting proteins, lipids, nucleic acids. In the context of neurodegenerative diseases, may carry toxic, misfolded forms amyloidogenic proteins facilitate their spread recipient in central nervous system (CNS). CNS-originating can cross blood–brain barrier into bloodstream be found other body fluids, saliva, tears, urine. originating CNS represent an attractive source biomarkers for because they contain cell- cell state-specific biological materials. recent years, multiple papers reported use this strategy identification quantitation Parkinson’s disease atypical parkinsonian disorders. However, certain technical issues yet standardized, such as best surface markers isolation type-specific validating cellular origin EVs. Here, we review research using biomarker studies, primarily disorders, highlight challenges, propose strategies overcoming them.

Language: Английский

Citations

59
Cell Type-Specific Extracellular Vesicles and Their Impact on Health and Disease DOI Open Access
Sohil Amin,

Hamed Massoumi,

Deepshikha Tewari

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2730 - 2730

Published: Feb. 27, 2024

Extracellular vesicles (EVs), a diverse group of cell-derived exocytosed particles, are pivotal in mediating intercellular communication due to their ability selectively transfer biomolecules specific cell types. EVs, composed proteins, nucleic acids, and lipids, taken up by cells affect variety signaling cascades. Research the field has primarily focused on stem with particular focus mesenchymal cells, for potential therapeutic benefits. Recently, tissue-specific EVs or type-specific extracellular (CTS-EVs), have garnered attention unique biogenesis molecular composition because they enable highly targeted cell-specific communication. Various studies outlined roles that CTS-EVs play physiological function maintenance homeostasis, including immune modulation, tissue regeneration, organ development. These properties also exploited disease propagation, such as cancer, neurological disorders, infectious diseases, autoimmune conditions, more. The insights gained from analyzing different biological not only enhance our understanding pathogenesis but open new avenues innovative diagnostic biomarkers targets wide spectrum medical conditions. This review comprehensively outlines current CTS-EV origins, within normal physiology, implications diseased states.

Language: Английский

Citations

20
Extracellular vesicles as personalized medicine DOI Creative Commons
Danielle J. Beetler, Damian N. Di Florio, Katelyn A. Bruno

et al.

Molecular Aspects of Medicine, Journal Year: 2022, Volume and Issue: 91, P. 101155 - 101155

Published: Nov. 28, 2022

Extracellular vesicles (EVs) are released from all cells in the body, forming an important intercellular communication network that contributes to health and disease. The contents of EVs cell source-specific, inducing distinct signaling responses recipient cells. specificity their accumulation fluid spaces accessible for liquid biopsies make them highly attractive as potential biomarkers therapies duality favorable (therapeutic) or unfavorable (pathological) messengers is context dependent remains be fully determined homeostasis various disease states. This review describes use biomarkers, drug delivery vehicles, regenerative therapeutics, highlighting examples involving viral infections, cancer, neurological diseases. There growing interest provide personalized therapy based on individual patient characteristics. Increasing evidence suggests EV therapeutic approaches ideal medicine due diversity multifunctionality EVs.

Language: Английский

Citations

56
TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia DOI Creative Commons
Amit Jairaman, Amanda McQuade, Alberto Granzotto

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Feb. 22, 2022

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of are associated with increased risk Alzheimer’s disease (AD). Because abnormalities in Ca 2+ signaling have been observed several AD models, we investigated regulation human induced pluripotent stem cell-derived microglia (iPSC-microglia) genetic deletion TREM2. We found that iPSC-microglia lacking (TREM2 KO) show exaggerated signals response to purinergic agonists, such as ADP, shape injury responses. This ADP hypersensitivity, driven by expression P2Y 12 13 receptors, results greater release from the endoplasmic reticulum stores, which triggers sustained influx through Orai channels alters cell motility KO microglia. Using expressing genetically encoded probe, Salsa6f, cytosolic tunes a extent Despite showing overall displacement, exhibit reduced directional chemotaxis along gradients. Accordingly, chemotactic defect was rescued reducing using receptor antagonist. Our loss confers signals, suggesting window for optimal motility.

Language: Английский

Citations

45
ATP1A3 as a target for isolating neuron-specific extracellular vesicles from human brain and biofluids DOI Creative Commons
Yang You, Zhengrong Zhang, Nadia Sultana

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(37)

Published: Sept. 15, 2023

Neuron-derived extracellular vesicles (NDEVs) are potential biomarkers of neurological diseases although their reliable molecular target is not well established. Here, we demonstrate that ATPase Na + /K transporting subunit alpha 3 (ATP1A3) abundantly expressed in (EVs) isolated from induced human neuron, brain, cerebrospinal fluid, and plasma comparison with the presumed NDEV markers NCAM1 L1CAM by using super-resolution microscopy biochemical assessments. Proteomic analysis immunoprecipitated ATP1A3 brain-derived EVs shows higher enrichment synaptic cargo proteins relevant to Alzheimer’s disease (AD) compared or LICAM EVs. Single particle elevated amyloid-β positivity AD plasma, providing better diagnostic prediction over other biomarkers. Thus, a isolate biofluids for research.

Language: Английский

Citations

33
Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders: Boom or Bust DOI Creative Commons
Ashish Kumar, Michael A. Nader, Gagan Deep

et al.

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 76(2), P. 199 - 227

Published: Dec. 19, 2023

Abstract

Extracellular vesicles (EVs) have emerged as an attractive liquid biopsy approach in the diagnosis and prognosis of multiple diseases disorders. The feasibility enriching specific subpopulations EVs from biofluids based on their unique surface markers has opened novel opportunities to gain molecular insight various tissues organs, including brain. Over past decade, bodily fluids been extensively studied for biomarkers associated with neurological disorders, such Alzheimer9s disease, Parkinson9s schizophrenia, bipolar disorder, major depressive substance use human immunodeficiency virus–associated neurocognitive cancer/treatment-induced neurodegeneration. These studies focused isolation cargo characterization either total or brain cells, neuron-, astrocyte-, microglia-, oligodendrocyte-, pericyte-, endothelial-derived achieve early predict treatment intervention outcomes. findings these demonstrated that could serve a repetitive less invasive source valuable information supplementing existing costly neuroimaging techniques relatively measures, like lumbar puncture. However, initial excitement surrounding blood-based brain-related tempered by challenges, lack central nervous system specificity EV markers, lengthy protocols, absence standardized procedures biological sample collection, isolation, characterization. Nevertheless, rapid advancements field, supported improved methods sensitive assays characterization, cell–derived continue offer unparallel significant translational implications

Significance Statement

present Characterizing holds potential yield information, thereby significantly impacting development This paper reviewed methodology employed isolate extracellular derived cells biofluids, utility enhancing understanding neurodegeneration, challenges this research field.

Language: Английский

Citations

32
Comprehensive characterization of human brain‐derived extracellular vesicles using multiple isolation methods: Implications for diagnostic and therapeutic applications DOI Creative Commons
Zhengrong Zhang, Kaiwen Yu, Yang You

et al.

Journal of Extracellular Vesicles, Journal Year: 2023, Volume and Issue: 12(8)

Published: Aug. 1, 2023

Abstract Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and promising biomarkers therapeutics in the central nervous system (CNS). Human brain‐derived EVs (BDEVs) provide a comprehensive snapshot physiological changes brain's environment, however, isolation BDEVs comparison different methods for this purpose not been fully investigated. In study, we compared yield, morphology, subtypes protein cargo composition isolated from temporal cortex aged human brains using three established separation methods: size‐exclusion chromatography (SEC), phosphatidylserine affinity capture (MagE) sucrose gradient ultracentrifugation (SG‐UC). Our results showed that SG‐UC method provided highest yield collected larger to SEC MagE assessed by transmission electron microscopy nanoparticle tracking analysis (NTA). Quantitative tandem mass‐tag (TMT) mass spectrometry EV samples identified total 1158 proteins, with showing best enrichment common proteins less contamination non‐EV proteins. addition, were enriched associated ATP activity CNS maintenance, abundant neuronal oligodendrocytic molecules. contrast, more molecules related lipoproteins, cell‐substrate junction microglia, whereas highly extracellular matrix, Alzheimer's disease astrocytes. Finally, validated proteomic performing single‐particle super‐resolution flow cytometry. Overall, our findings demonstrate differences size, single assay methods, suggesting choice will significant impact on downstream discovery.

Language: Английский

Citations

31