Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

Laulagnier, Karine; Javalet, Charlotte; Hemming, Fiona J.; Chivet, Mathilde; Lachenal, Gaëlle; Blot, Béatrice; Chatellard, Christine; Sadoul, Rémy

doi:10.1007/s00018-017-2664-0

Cited by 125 publications

(111 citation statements)

References 72 publications

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“…Recently, it has been found that N2a cells carrying the autosomal-dominant Swedish form of APP (KM670/671NL) secreted exosomes containing Aβ and C-terminal fragments of APP whereas cells expressing wildtype APP secreted exosomes that contained the APP Cterminal fragments but not Aβ. Furthermore, APP and its C-terminal fragments were specifically sorted into exosomes lacking the tetraspanin protein CD63, demonstrating that neuroblastoma cells secrete distinct populations of exosomes containing different cargos and targeting specific cell types (Laulagnier et al, 2018).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

Hornung

Dutta

Bitan

2020

Front. Mol. Neurosci.

163

159

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Eukaryotic cells release different types of extracellular vesicles (EVs) including exosomes, ectosomes, and microvesicles. Exosomes are nanovesicles, 30-200 nm in diameter, that carry cell-and cell-state-specific cargo of proteins, lipids, and nucleic acids, including mRNA and miRNA. Recent studies have shown that central nervous system (CNS)-derived exosomes may carry amyloidogenic proteins and facilitate their cell-to-cell transfer, thus playing a critical role in the progression of neurodegenerative diseases, such as tauopathies and synucleinopathies. CNS-derived exosomes also have been shown to cross the blood-brain-barrier into the bloodstream and therefore have drawn substantial attention as a source of biomarkers for various neurodegenerative diseases as they can be isolated via a minimally invasive blood draw and report on the biochemical status of the CNS. However, although isolating specific brain-cell-derived exosomes from the blood is theoretically simple and the approach has great promise, practical details are of crucial importance and may compromise the reproducibility and utility of this approach, especially when different laboratories use different protocols. In this review we discuss the role of exosomes in neurodegenerative diseases, the usefulness of CNS-derived blood exosomes as a source of biomarkers for these diseases, and practical challenges associated with the methodology of CNS-derived blood exosomes and subsequent biomarker analysis.

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Section: Alzheimer's Diseasementioning

confidence: 99%

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

Hornung

Dutta

Bitan

2020

Front. Mol. Neurosci.

163

159

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“…In AD, EVs have been proposed to contribute to the spread of Aβ and Aβ pathology in the brain (Rajendran et al, 2006) as well as the spread of hyper-phosphorylated pathogenic tau between neurons (Saman et al, 2012;Wang et al, 2017;Guix et al, 2018;Winston et al, 2019). We and others have shown that EVs contain full-length APP, the CTFs of APP generated through cleavage by β-secretase (βCTFs) or α-secretase (αCTFs), Aβ, and the enzymes that are responsible for these cleavage steps (Rajendran et al, 2006;Vingtdeux et al, 2007;Escrevente et al, 2008;Sharples et al, 2008;Pérez-González et al, 2012;Laulagnier et al, 2018;Miranda et al, 2018). The endosomal pathway is critical for the processing of APP (Nixon, 2017), with β-secretase cleavage mediated by BACE1 occurring in endosomes (Koo, 2002;Kinoshita et al, 2003;Small and Gandy, 2006).…”

Section: Potential Contribution Of Evs To the Spread Of Pathogenic Momentioning

confidence: 99%

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

Mathews

Levy

2019

Front. Neurosci.

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“…We found that the purified EV fraction from S2 cell supernatants met these criteria (Fig 1E, F) the ratio of an EGFP-tagged C-terminal fragment of APP (CTF) compared to full-length APP was greatly enhanced in the S2 cell EV fraction relative to total cell extracts, while EGFP alone did not fractionate with EVs. Indeed, S2 cells have been previously shown to express proteases capable of processing APP family members (Luo et al, 1990), and similar CTFs of endogenous APP are enriched in EVs derived from cortical neurons (Laulagnier et al, 2017). Taken together, these results indicate that APP-EGFP, and particularly a CTF of this protein, is trafficked into EVs by multiple established criteria (Thery et al, 2018).…”

Section: Neuronally-expressed App Traffics Into Evs In Neuronsmentioning

confidence: 74%

“…APP is a type I transmembrane protein that traffics through the endosomal system, where it can be proteolytically processed into fragments including toxic Amyloid-b (Ab), a major constituent of the hallmark amyloid plaques of Alzheimer's Disease (Tan and Gleeson, 2019). APP C-terminal fragments and Ab have been found in pathogenic EVs (Laulagnier et al, 2017;Perez-Gonzalez et al, 2012;Rajendran et al, 2006;Sardar Sinha et al, 2018;Sharples et al, 2008), but the mechanisms by which APP is sorted into EVs are not well understood, and are challenging to study in vivo at synapses, which may be important sites of Ab release (Brodin and Shupliakov, 2018;Dolev et al, 2013;Lazarov et al, 2002;Lundgren et al, 2014;Schedin-Weiss et al, 2016;Yu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Opposing functions for retromer and Rab11 in extracellular vesicle cargo traffic at presynaptic terminals

Walsh

Becalska

Zunitch

et al. 2019

Preprint

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Neuronal extracellular vesicles (EVs) play critical roles in intercellular communication and in propagation of pathogenic proteins in neurological disease. However, little is known about how cargoes are selectively packaged into neuronal EVs. Here, we examined the intracellular traffic and release of the EV cargoes Amyloid Precursor Protein (APP) and Synaptotagmin-4 (Syt4) at presynaptic nerve terminals of Drosophila motor neurons. We found that loss of the endosomal retromer complex leads to increased EV cargo levels both presynaptically and in EVs, and that this function is separable from previously identified roles of neuronal retromer. Conversely, EV cargo levels are reduced in rab11 mutants, and EV cargo sorting depends on a balance between Rab11-mediated recycling and retromer-dependent removal from the EV pathway. Rab11 and retromer have previously been implicated in Alzheimer's Disease, suggesting that these competing pathways may serve as therapeutic targets for limiting accumulation and release of toxic EV cargoes.

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Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

Cited by 125 publications

References 72 publications

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

Opposing functions for retromer and Rab11 in extracellular vesicle cargo traffic at presynaptic terminals

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