The role of exosomes in the pathogenesis of Alzheimer’ disease

Xiao, Tingting; Zhang, Weiwei; Jiao, Bin; Pan, Chuzheng; Liu, Xixi; Shen, Lu

doi:10.1186/s40035-017-0072-x

Cited by 114 publications

(96 citation statements)

References 76 publications

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“…Recent studies have demonstrated the usefulness of this novel biomarker technology for prognosis as well as biological mechanisms for AD in the general population (Paschon et al 2016; Rajendran et al 2006; Riancho et al 2017; Sharples et al 2008; Vingtdeux et al 2012; Xiao et al 2017; Yuyama and Igarashi 2017), and can also be used for studying the propagation of pathology within the brain (Polanco et al 2016; Winston et al 2016). We are hopeful that this novel methodology can shed light on early events in the pathology in DS-AD and hopefully lead to novel intervention or prevention therapies.…”

Section: Discussionmentioning

confidence: 99%

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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Every person with Down syndrome (DS) has the characteristic features of Alzheimer’s disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

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Section: Discussionmentioning

confidence: 99%

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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“…In the heart, cardiomyocytes-derived exosomes can transfer functional glucose transporters and glycolytic enzymes to modulate glucose transport and metabolism in recipient endothelial cells [70]. Microglia can spread protein via exosome secretion and depletion of microglia or inhibition of exosome synthesis was shown to significantly reduce tau propagation in vitro and in vivo [71, 72]. In RPE-endothelial cell interactions, it was demonstrated that ethanol-stressed RPE cells release more exosomes than control cells, and those exosomes contain higher levels of VEGF receptors in their membranes, as well as increased levels of VEGFR-1 and −2 mRNA within the exosome and thus promote vasculogenesis/angiogenesis when they interact with endothelial cells [73].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle-mediated long-range communication in stressed retinal pigment epithelial cell monolayers

Shah

Ishii

Brandon

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Retinal pigment epithelium (RPE) alterations in age-related macular degeneration occur in patches, potentially involving long-distance communication between damaged and healthy areas. Communication along the epithelium might be mediated by extracellular vesicles (EVs). To test this hypothesis, EVs were collected from supernatants of polarized ARPE-19 and primary porcine RPE monolayers for functional and biochemical assays. EVs from oxidatively stressed donor cells reduced barrier function in recipient RPE monolayers when compared to control EVs. The effect on barrier function was dependent on EV uptake, which occurred rapidly with EVs from oxidatively stressed donor cells. Mass spectrometry-based proteomic analysis of EVs identified HDAC6, which is known to reduce tight junction stability. Activity assays confirmed the presence of HDAC6 in EVs, and EV transfer assays using HDAC6 inhibitors confirmed its effect in monolayers. These findings demonstrate that EVs can communicate stress messages to healthy RPE cells, potentially contributing to RPE dysfunction.

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“…Recent studies indicate that myeloid cells can release EVs/MP that spread inflammatory signals both in vitro and in vivo to alter neuronal functions (Harrison-Brown et al, 2016;Nigro et al, 2016;Beneventano et al, 2017;Kumar et al, 2017). Importantly, EV levels are significantly increased following TBI in humans and animal models, as well as in chronic neurodegenerative and autoimmune disorders such as Alzheimer's disease (AD) and multiple sclerosis, supporting the concept that spreading inflammation via EVs release may play a role in these neuropathologies (Taylor and Gercel-Taylor, 2014;Xiao et al, 2017;Pieragostino et al, 2018). Thus, nSMase inhibitors have emerged as new pharmacological agents for preventing release of EVs and thus can modulate inflammation and oxidative stress.…”

Section: Introductionmentioning

confidence: 93%

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

Kumar

Henry

Stoica

et al. 2018

J Pharmacol Exp Ther

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Neuroinflammation is one of the key secondary injury mechanisms triggered by traumatic brain injury (TBI). Microglial activation, a hallmark of brain neuroinflammation, plays a critical role in regulating immune responses after TBI and contributes to progressive neurodegeneration and neurologic deficits following brain trauma. Here we evaluated the role of neutral sphingomyelinase (nSMase) in microglial activation by examining the effects of the nSMase inhibitors altenusin and GW4869 in vitro (using BV2 microglia cells and primary microglia), as well as in a controlled cortical injury (CCI) model in adult male C57BL/6 mice. Pretreatment of altenusin or GW4869 prior to lipopolysaccharide (LPS) stimulation for 4 or 24 hours, significantly downregulated gene expression of the pro-inflammatory mediators TNF-a, IL-1b, IL-6, iNOS, and CCL2 in microglia and reduced the release of nitric oxide and TNF-a. These nSMase inhibitors also attenuated the release of microparticles and phosphorylation of p38 MAPK and ERK1/2. In addition, altenusin pretreatment also reduced the gene expression of multiple inflammatory markers associated with microglial activation after experimental TBI, including TNF-a, IL-1b, IL-6, iNOS, CCL2, CD68, NOX2, and p22 phox . Overall, our data demonstrate that nSMase inhibitors attenuate multiple inflammatory pathways associated with microglial activation in vitro and after experimental TBI. Thus, nSMase inhibitors may represent promising therapeutics agents targeting neuroinflammation.

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The role of exosomes in the pathogenesis of Alzheimer’ disease

Cited by 114 publications

References 76 publications

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Extracellular vesicle-mediated long-range communication in stressed retinal pigment epithelial cell monolayers

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

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