Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity

Nogueras-Ortiz, Carlos; Mahairaki, Vasiliki; Delgado-Peraza, Francheska; Das, Debamitra; Avgerinos, Konstantinos I.; Hentschel, Matthew; Goetzl, Edward J.; Mattson, Mark P.; Kapogiannis, Dimitrios

doi:10.1101/2020.04.14.041863

Cited by 19 publications

(8 citation statements)

References 76 publications

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“…The study that measured betaIII-tubulin immunoselected using an antibody raised to a luminal L1CAM epitope (Zou et al, 2020), which may complicate interpretation. Another study detected glial fibrillary acidic protein (GFAP) in putative L1CAM+ material (Nogueras-Ortiz et al, 2020), an unexpected result. Finally, a proteomics study of L1CAM capture identified two proteins that were significantly enriched in brain, but also found significant enrichment of components of common contaminants of EV preparations, including circulating IgG complexes, HDL, very low-density lipoproteins (VLDL) and chylomicrons (Winston et al, 2016).…”

Section: Negative/depleted Non-ev Markersmentioning

confidence: 93%

“…Five studies that did not specifically combine L1CAM and EVs were also removed. A total of 51 articles thus satisfied all criteria (see Figure 1 and list of papers in Table S1) (Anastasi et al, 2021;Athauda et al, 2019;Bhargava et al, Goetzl et al, 2019;Goetzl et al, 2015;Goetzl, Peltz, Mustapic, Kapogiannis, & Yaffe, 2020;Gomes et al, 2015;Gu et al, 2020;Gutwein et al, 2003;Gutwein et al, 2005;Herrero et al, 2019;Jiang et al, 2020;Jiang et al, 2021;Keller et al, 2009;Kodidela et al, 2020;Kumar et al, 2021;Mansur et al, 2021;Mullins, Mustapic, Goetzl, & Kapogiannis, 2017;Nasca et al, 2021;Nogueras-Ortiz et al, 2020;Norman et al, 2021;Pace, Dutt, & Galileo, 2019;Patterson, Deep, & Brinkley, 2018;Peltz et al, 2020;Pulliam, Liston, Sun, & Narvid, 2020;Rani et al, 2019;Shi et al, 2016;Shi et al, 2014;Si et al, 2019;Stoeck et al, 2006;Suire et al, 2017;Sun, Dalvi, Abadjian, Tang, & Pulliam, 2017;Sun, Fernandes, & Pulliam, 2019;Trnka, Ivanova, Hiatt, & Matsell, 2012;Walker et al, 2021;Webber et al, 2014;Winston et al, 2019;Winston et al, 2016;…”

Section:  Literature Search and Selectionmentioning

confidence: 96%

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L1CAM‐associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization

Gomes

Witwer

2022

J of Extracellular Bio

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When released into biological fluids like blood or saliva, brain extracellular vesicles (EVs) might provide a window into otherwise inaccessible tissue, contributing useful biomarkers of neurodegenerative and other central nervous system (CNS) diseases. To enrich for brain EVs in the periphery, however, cell-specific EV surface markers are needed. The protein that has been used most frequently to obtain EVs of putative neuronal origin is the transmembrane L1 cell adhesion molecule (L1CAM/CD171). In this systematic review, we examine the existing literature on L1CAM and EVs, including investigations of both neurodegenerative disease and cancer through the lens of the minimal information for studies of EVs (MISEV), specifically in the domains of nomenclature usage, EV sources, and EV separation and characterization. Although numerous studies have reported L1CAM-associated biomarker signatures that correlate with disease, interpretation of these results is complicated since L1CAM expression is not restricted to neurons and is also upregulated during cancer progression. A recent study has suggested that L1CAM epitopes are present in biofluids mostly or entirely as cleaved, soluble protein. Our findings on practices and trends in L1CAM-mediated EV separation, enrichment, and characterization yield insights that may assist with interpreting results, evaluating rigor, and suggesting avenues for further exploration.

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Section: Negative/depleted Non-ev Markersmentioning

confidence: 93%

Section:  Literature Search and Selectionmentioning

confidence: 96%

L1CAM‐associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization

Gomes

Witwer

2022

J of Extracellular Bio

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“…High complement levels can also be found in astrocytic EVs and neuronal EVs (Goetzl et al, 2018). These inflammatory EVs cause cellular membrane disruption and neurite density reduction in rat cortical neurons by activating membrane attack complex (MAC) formation (Nogueras-Ortiz et al, 2020). Age-associated chronic inflammatory states are similarly evident during PD progression.…”

Section:  Neurodegenerationmentioning

confidence: 99%

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Yin

Chen

Wang

et al. 2021

J of Extracellular Vesicle

103

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Cellular senescence is a persistently hypoproliferative state with diverse stressors in a specific aging microenvironment. Senescent cells have a double-edged sword effect: they can be physiologically beneficial for tissue repair, organ growth, and body homeostasis, and they can be pathologically harmful in age-related diseases. Among the hallmarks of senescence, the SASP, especially SASP-related extracellular vesicle (EV) signalling, plays the leading role in aging transmission via paracrine and endocrine mechanisms. EVs are successful in intercellular and interorgan communication in the aging microenvironment and age-related diseases. They have detrimental effects on downstream targets at the levels of immunity, inflammation, gene expression, and metabolism. Furthermore, EVs obtained from different donors are also promising materials and tools for antiaging treatments and are used for regeneration and rejuvenation in cell-free systems. Here, we describe the characteristics of cellular senescence and the aging microenvironment, concentrating on the production and function of EVs in age-related diseases, and provide new ideas for antiaging therapy with EVs.

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“…For instance, it was shown that astrocyte-derived EVs from plasma of AD patients and patients with mild cognitive impairment (MCI) who are converting to dementia contain significantly higher complement levels compared to controls and stable MCI patients [ 40 , 41 ]. Furthermore, astrocyte-derived EVs separated from plasma of AD patients exert neurotoxicity in neuronal cultures due to their high levels of several complement proteins [ 42 ]. The complement system is a rapid and efficient immune surveillance system, but when imbalanced it contributes to a variety of disorders including AD [ 43 , 44 ].…”

Section: Introductionmentioning

confidence: 99%

Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease

Vandendriessche

Balusu

Cauwenberghe

et al. 2021

acta neuropathol commun

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Increasing evidence indicates that extracellular vesicles (EVs) play an important role in the pathogenesis of Alzheimer’s disease (AD). We previously reported that the blood–cerebrospinal fluid (CSF) interface, formed by the choroid plexus epithelial (CPE) cells, releases an increased amount of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-mediated EV release in AD pathogenesis. We observed increased EV levels in the CSF of young transgenic APP/PS1 mice which correlated with high amyloid beta (Aβ) CSF levels at this age. The intracerebroventricular (icv) injection of Aβ oligomers (AβO) in wild-type mice revealed a significant increase of EVs in the CSF, signifying that the presence of CSF-AβO is sufficient to induce increased EV secretion. Using in vivo, in vitro and ex vivo approaches, we identified the CP as a major source of the CSF-EVs. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures. Proteome analysis of these EVs revealed the presence of several pro-inflammatory proteins, including the complement protein C3. Strikingly, inhibition of EV production using GW4869 resulted in protection against acute AβO-induced cognitive decline. Further research into the underlying mechanisms of this EV secretion might open up novel therapeutic strategies to impact the pathogenesis and progression of AD.

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Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity

Cited by 19 publications

References 76 publications

L1CAM‐associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization

L1CAM‐associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease

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