C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease

García‐Ayllón, María‐Salud; López-Font, Inmaculada; Boix, Claudia P.; Fortea, Juan; Castilla, Joaquı́n; Lleó, Alberto; Molinuevo, José Luís; Zetterberg, Henrik; Blennow, Kaj; Sáez‐Valero, Javier

doi:10.1038/s41598-017-02841-7

Cited by 34 publications

(27 citation statements)

References 32 publications

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“…Interestingly, the presence of C99 in AD-neuron derived exosomes opens up the possibility to use this as an early biomarker. Indeed, mouse models of AD demonstrate that C99-containing exosomes appear at early stage of disease and similar observations have been made in AD patient brain tissues and CSF [32,56,187]. Similarly, lysosomal proteins levels (such as cathepsin D and LAMP-1) as well as autophagic proteins (e.g., p62) are altered in neuron-derived exosomes from AD models or patients, which is reflective of the lysosomal dysfunction that is associated with AD [64,137,188].…”

Section: Transmissible Endosomal Intoxication (Tei)supporting

confidence: 63%

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

2020

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In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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Section: Transmissible Endosomal Intoxication (Tei)supporting

confidence: 63%

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

2020

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“…Our study suggests that detection of BMP in bodily fluids, such as blood, cerebrospinal fluid (CSF), and urine, may be more indicative of exosomal secretion in response to LSD than a simple measure of phospholipidosis 66 . APP-CTFs have also been reported in human CSF 67 , suggesting that they can be helpful biomarkers in clinical settings. In sum, APP-CTFs and BMP should be explored as exosome-related biomarkers for a range of neurodegenerative disorders, including AD, PD, LBD, FTD, ALS, and many LSDs.…”

Section: Discussionmentioning

confidence: 99%

Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

et al. 2018

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Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.

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“…Thus, the existence of a membrane-resident protein in CSF is not an unusual finding [ 46 ]. Recently, we also characterized in CSF the existence of C-terminal fragments of APP, which include the transmembrane domain [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Levels of ADAM10 are reduced in Alzheimer’s disease CSF

Sogorb‐Esteve

García‐Ayllón

Gobom

et al. 2018

J Neuroinflammation

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BackgroundThe disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of the amyloid precursor protein. This study assesses whether ADAM10 is present in cerebrospinal fluid (CSF), and whether it has potential as a biomarker for Alzheimer’s disease (AD).MethodsADAM10 was characterized in human CSF samples by immunoprecipitation and western blotting using antibodies specific for different domains of the protein and by ultracentrifugation in sucrose density gradients. Samples from AD patients (n = 20) and age-matched non-AD controls (n = 20) were characterized for classical CSF biomarkers, Aβ42, T-tau, or P-tau by ELISA, and assayed for soluble ADAM10 levels by western blotting.ResultsWe found that ADAM10 is present in human CSF as several distinct species: an immature form retaining the prodomain (proADAM10; ~ 80 kDa), a mature unprocessed full-length form (ADAM10f; ~ 55 kDa), and a truncated large soluble form released from the membrane (sADAM10; ~ 50 kDa). Fractionation by ultracentrifugation on sucrose density gradients showed that the ADAM10f and sADAM10 species form large complexes. Immunoblotting revealed a significant decrease in ADAM10f and sADAM10 in AD CSF compared to control CSF, while proADAM10 levels remained unaltered.ConclusionsSeveral forms of ADAM10 are present in CSF, mainly assembled as high-molecular weight complexes. The determination of the levels of mature forms of CSF-ADAM10 may be useful as a biomarker for AD.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1255-9) contains supplementary material, which is available to authorized users.

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C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease

Cited by 34 publications

References 32 publications

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Levels of ADAM10 are reduced in Alzheimer’s disease CSF

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