Plasma Exosomes Spread and Cluster Around β-Amyloid Plaques in an Animal Model of Alzheimer’s Disease

Zheng, Tingting; Pu, Jiali; Chen, Yanxing; Mao, Yanfang; Guo, Zhangyu; Pan, Hongyu; Zhang, Ling; Zhang, Heng; Sun, Binggui; Zhang, Baorong

doi:10.3389/fnagi.2017.00012

Cited by 64 publications

(62 citation statements)

References 64 publications

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“…The study of exosomes in disease could provide important clues to the progression of neurodegenerative diseases and cancer. Previous studies provided evidence that amyloids involved in Alzheimer's disease, such as amyloid β, are released via exosomes and that exosome‐associated amyloids can act as seeds for plaque formation . Release of brain tumor vesicles and uptake by normal cells are associated with progression, angiogenesis, tumor cell invasion, and suppression of immune responses to the tumor.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc‐MKRN2‐42:1 in the pathogenesis of Parkinson's disease

et al. 2019

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Background: Parkinson's disease (PD) is a common movement disorder for which diagnosis mainly depends on the medical history and clinical symptoms. Exosomes are now considered an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids, and genetic material. Long noncoding (lnc) RNA in exosomes plays a critical role in many diseases, including neurodegenerative disease.Aim: To study expression differences for lncRNAs in peripheral blood exosomes of PD patients compared with healthy individuals and to look for lncRNAs that might be related to the pathogenesis of PD. Materials and Methods:We recruited PD patients along with age-and sex-matched healthy individuals as healthy controls and evaluated levels of lncRNAs extracted from exosomes in plasma samples via next-generation sequencing and real-time quantitative PCR. Correlation analysis was conducted for the clinical characteristics of PD patients and the expression of selected lncRNAs.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc‐MKRN2‐42:1 in the pathogenesis of Parkinson's disease

et al. 2019

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“…The nuclear localization of mutant Htt in astrocytes led us to investigate whether mHtt affects the transcription of molecules that are important for the release of exosomes. Previous studies show that ␣B-crystallin, which mediates exosome secretion (Gangalum et al, 2016), is decreased in HD mouse models, such as R6/2 and BACHD mice (Zabel et al, 2002;Oliveira et al, 2016). When comparing the expression of ␣B-crystallin in cultured astrocytes and neurons, we found that ␣B-crystallin is much more abundant in astrocytes (Fig.…”

Section: Mhtt Impairs ␣B-crystallin Expression Both In Cultured Astromentioning

confidence: 58%

“…Although ␣B-crystallin is decreased in HD mouse brains (Zabel et al, 2002;Oliveira et al, 2016), the mechanism underlying this decrease remains unknown. Because mRNA levels of ␣B-crystallin are reduced in HD KI astrocytes, we hypothesized that mHtt inhibits ␣B-crystallin transcription by affecting its promoter activity.…”

Section: Sp1 Mediates ␣B-crystallin Expression In Astrocytesmentioning

confidence: 99%

“…To confirm the effect of ␣B-crystallin overexpression in vivo, we used ␣B-crystallin-V5 adenovirus for overexpression in the striatum of HD KI mice via stereotaxic injection. Expression of ␣B-crystallin-V5 was driven by the CMV promoter, which has high tropism toward astrocytes in the mouse brain (Iino et al, 2001;Yue et al, 2005;. We isolated exosomes from the striatum of HD KI mice 30 d after stereotaxic injection.…”

Section: ␣B-crystallin Overexpression Rescues Defective Exosome Secrementioning

confidence: 99%

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Mutant Huntingtin Inhibits αB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes

Hong

Zhao

2017

J. Neurosci.

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In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes. We found that mHtt is not present in astrocytic exosomes, but can decrease exosome secretion from astrocytes in HD140Q knock-in (KI) mice. N-terminal mHtt accumulates in the nuclei and forms aggregates, causing decreased secretion of exosomes from cultured astrocytes. Consistently, there is a significant decrease in secreted exosomes in both female and male HD KI mouse striatum in which abundant nuclear mHtt aggregates are present. Conversely, injection of astrocytic exosomes into the striatum of HD140Q KI mice reduces the density of mHtt aggregates. Further, mHtt in astrocytes decreased the expression of αB-crystallin, a small heat shock protein that is enriched in astrocytes and mediates exosome secretion, by reducing the association of Sp1 with the enhancer of the α gene. Importantly, overexpression of αB-crystallin rescues defective exosome release from HD astrocytes as well as mHtt aggregates in the striatum of HD140Q KI mice. Our results demonstrate that mHtt reduces the expression of αB-crystallin in astrocytes to decrease exosome secretion in the HD brains, contributing to non-cell-autonomous neurotoxicity in HD. Huntington's disease (HD) is characterized by selective neurodegeneration that preferentially occurs in the striatal medium spiny neurons. Recent studies in different HD mouse models demonstrated that dysfunction of astrocytes, a major type of glial cell, leads to neuronal vulnerability. Emerging evidence shows that exosomes secreted from astrocytes contain neuroprotective cargoes that could support the survival of neighboring neurons. We found that mHtt in astrocytes impairs exosome secretion by decreasing αB-crystallin, a protein that is expressed mainly in glial cells and mediates exosome secretion. Overexpression of αB-crystallin could alleviate the deficient exosome release and neuropathology in HD mice. Our results revealed a new pathological pathway that affects the critical support of glial cells to neurons in the HD brain.

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“…The protein cargo derived from EVs isolated from AD patients has provided valued insight with respect to identifying potential ongoing pathological processes in the brains of individuals with preclinical and clinically diagnosed AD (Goetzl et al, ; Goetzl et al, ; Goetzl et al, ). In a mouse model of AD, serum‐derived EVs cluster around amyloid‐beta (Aβ) plaques and localize to microglia (Zheng et al, ). In this study, AD, but not normal ageing, was associated with a reduced capacity for microglia to internalize EVs.…”

Section: Novel Roles Of Mirnas As Intercellular Signaling Molecules Wmentioning

confidence: 99%

The roles of extracellular vesicle microRNAs in the central nervous system

Blandford

Galloway

Moore

2018

Glia

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MicroRNAs (miRNAs) are small, highly conserved non-coding RNA molecules that post-transcriptionally regulate protein expression and most biological processes. Mature miRNAs are recruited to the RNA-induced silencing complex (RISC) and target mRNAs via complementary base-pairing, thus resulting in translational inhibition and/or transcript degradation. Here, we present evidence implicating miRNAs within extracellular vesicles (EVs), including microvesicles and exosomes, as mediators of central nervous system (CNS) development, homeostasis, and injury. EVs are extracellular vesicles that are secreted by all cells and represent a novel method of intercellular communication. In glial cells, the transfer of miRNAs via EVs can alter the function of recipient cells and significantly impacts cellular mechanisms involved in both injury and repair. This review discusses the value of information to be gained by studying miRNAs within EVs in the context of CNS diseases and their potential use in the development of novel disease biomarkers and therapeutic strategies.

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Plasma Exosomes Spread and Cluster Around β-Amyloid Plaques in an Animal Model of Alzheimer’s Disease

Cited by 64 publications

References 64 publications

Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc‐MKRN2‐42:1 in the pathogenesis of Parkinson's disease

Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc‐MKRN2‐42:1 in the pathogenesis of Parkinson's disease

Mutant Huntingtin Inhibits αB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes

The roles of extracellular vesicle microRNAs in the central nervous system

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