ADAM10 as a Biomarker for Alzheimer’s Disease: A Study with Brazilian Elderly

Manzine, Patrícia Regina; Bram, Jessyka Maria de França; Barham, Elisabeth Joan; Vale, Francisco de Assis Carvalho do; Selistre-de-Araújo, Heloísa Sobreiro; Cominetti, Márcia Regina; Pavarini, Sofía Cristina Iost

doi:10.1159/000345983

Cited by 46 publications

(37 citation statements)

References 47 publications

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“…Both ADAM10 and ADAM17 have been implicated in the development of neurodegenerative diseases such as Alzheimer’s disease [25, 58, 59]. Studies have also shown that ADAM10 expression is widespread in the CNS compared to a more restricted ADAM17 expression [31].…”

Section: Discussionmentioning

confidence: 99%

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

O’Sullivan

Gasparini

Mir

et al. 2016

J Neuroinflammation

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BackgroundThe fractalkine (CX3CR1) ligand is expressed in astrocytes and reported to be neuroprotective. When cleaved from the membrane, soluble fractalkine (sCX3CL1) activates the receptor CX3CR1. Although somewhat controversial, CX3CR1 is reported to be expressed in neurons and microglia. The membrane-bound form of CX3CL1 additionally acts as an adhesion molecule for microglia and infiltrating white blood cells. Much research has been done on the role of fractalkine in neuronal cells; however, little is known about the regulation of the CX3CL1 ligand in astrocytes.MethodsThe mechanisms involved in the up-regulation and cleavage of CX3CL1 from human astrocytes were investigated using immunocytochemistry, Q-PCR and ELISA. All statistical analysis was performed using GraphPad Prism 5.ResultsA combination of ADAM17 (TACE) and ADAM10 protease inhibitors was found to attenuate IL-1β-, TNF-α- and IFN-γ-induced sCX3CL1 levels in astrocytes. A specific ADAM10 (but not ADAM17) inhibitor also attenuated these effects, suggesting ADAM10 proteases induce release of sCX3CL1 from stimulated human astrocytes. A p38 MAPK inhibitor also attenuated the levels of sCX3CL1 upon treatment with IL-1β, TNF-α or IFN-γ. In addition, an IKKβ inhibitor significantly reduced the levels of sCX3CL1 induced by IL-1β or TNF-α in a concentration-dependent manner, suggesting a role for the NF-kB pathway.ConclusionsIn conclusion, this study shows that the release of soluble astrocytic fractalkine is regulated by ADAM10 proteases with p38 MAPK also playing a role in the fractalkine shedding event. These findings are important for understanding the role of CX3CL1 in healthy and stimulated astrocytes and may benefit our understanding of this pathway in neuro-inflammatory and neurodegenerative diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0659-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

O’Sullivan

Gasparini

Mir

et al. 2016

J Neuroinflammation

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“…Studies have shown a reduction of α-secretase protein level in platelets of early stage AD patients [30, 144], in line with attenuated release of sAPP-α from thrombin-activated AD platelets [145]. In addition, an increased activity of β-secretase was indirectly shown by a decreased ratio of its 37/56 kDa fragments from two different groups [143, 144].…”

Section: Reviewmentioning

confidence: 99%

Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers?

Veitinger

Varga

Guterres

et al. 2014

acta neuropathol commun

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Peripheral biomarkers play an indispensable role in quick and reliable diagnoses of any kind of disease. With the population ageing, the number of people suffering from age-related diseases is expected to rise dramatically over the coming decades. In particular, all types of cognitive deficits, such as Alzheimer’s disease, will increase. Alzheimer’s disease is characterised mainly by coexistence of amyloid plaques and neurofibrillary tangles in brain. Reliable identification of such molecular characteristics antemortem, however, is problematic due to restricted availability of appropriate sample material and definitive diagnosis is only possible postmortem. Currently, the best molecular biomarkers available for antemortem diagnosis originate from cerebrospinal fluid. Though, this is not convenient for routine diagnosis because of the required invasive lumbar puncture. As a consequence, there is a growing demand for additional peripheral biomarkers in a more readily accessible sample material. Blood platelets, due to shared biochemical properties with neurons, can constitute an attractive alternative as discussed here. This review summarises potential platelet Alzheimer’s disease biomarkers, their role, implication, and alteration in the disease. For easy comparison of their performance, the Hedge effect size was calculated whenever data were available.

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“…In previous studies we have reported a marked reduction in ADAM10 platelet protein levels in CDR (Clinical Dementia Rating) subgroups compared to non-AD patients (Colciaghi et al, 2002;Manzine et al, 2013) and APP, BACE1 and ADAM10 alterations in platelets already in the very early stages of the disease in which dementia can be barely inferred by neuropsychological assessments (Colciaghi et al, 2004). Since ADAM10 is the most important a-secretase involved in APP cleavage, in this work we raise the following question: is ADAM10 protein reduction in the blood of AD patients a consequence of a decrease in ADAM10 transcription?…”

Section: Introductionmentioning

confidence: 94%

ADAM10 gene expression in the blood cells of Alzheimer's disease patients and mild cognitive impairment subjects

et al. 2015

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ADAM10 is a potential biomarker for Alzheimer's disease (AD). ADAM10 protein levels are reduced in platelets of AD patients. The aim was to verify the total blood and platelet ADAM10 gene expression in AD patients and to compare with mild cognitive impairment (MCI) and healthy subjects. No significant differences in ADAM10 gene expression were observed. Therefore, the decrease of ADAM10 protein in platelets of AD patients is not caused by a reduction in ADAM10 mRNA. Further studies must be performed to investigate other pathways in the down regulation of ADAM10 protein.

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ADAM10 as a Biomarker for Alzheimer’s Disease: A Study with Brazilian Elderly

Cited by 46 publications

References 47 publications

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers?

ADAM10 gene expression in the blood cells of Alzheimer's disease patients and mild cognitive impairment subjects

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