Levels of ADAM10 are reduced in Alzheimer\u2019s disease CSF

Aitana Sogorb-Esteve,Javier Sáez-Valero,Johan Gobom,Jordi Alom,Henrik Zetterberg,María-Salud García-Ayllón,Kaj Blennow

doi:10.1186/s12974-018-1255-9

Abstract

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.

Highlights

The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of the amyloid precursor protein
To our knowledge, only ADAM17/TACE activity has been assessed in both cerebrospinal fluid (CSF) [19] and plasma [20, 21]; while the potential of Disintegrin metalloproteinase 10 (ADAM10) as an alternative Alzheimer’s disease (AD) biomarker has so far only been investigated in platelets [22, 23] and other blood cells [24]
We investigated the occurrence of ADAM10 in human CSF and whether altered levels of this protein occur in AD

Summary

Introduction

The 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). Aβ is a short polypeptide generated by processing of a larger type I transmembrane spanning glycoprotein, the amyloid precursor protein (APP), through the successive action of proteolytic enzymes called β-secretase and γ-secretase [2, 3]. To our knowledge, only ADAM17/TACE activity has been assessed in both CSF [19] and plasma [20, 21]; while the potential of ADAM10 as an alternative AD biomarker has so far only been investigated in platelets [22, 23] and other blood cells [24].

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