Dataset Information

Levels of ADAM10 are reduced in Alzheimer's disease CSF.

ABSTRACT:

Background

The disintegrin metalloproteinase 10 (ADAM10) is the main ?-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).

Methods

ADAM10 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, A?42, T-tau, or P-tau by ELISA, and assayed for soluble ADAM10 levels by western blotting.

Results

We 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.

Conclusions

Several 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.

SUBMITTER: Sogorb-Esteve A

PROVIDER: S-EPMC6060469 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Levels of ADAM10 are reduced in Alzheimer's disease CSF.

Sogorb-Esteve Aitana A García-Ayllón María-Salud MS Gobom Johan J Alom Jordi J Zetterberg Henrik H Blennow Kaj K Sáez-Valero Javier J

Journal of neuroinflammation 20180725 1

<h4>Background</h4>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).<h4>Methods</h4>ADAM10 was characterized in human CSF samples by immunoprecipitation and western blotting using antibodies specific for different domains of the protein and by ultracent ...[more]

PMID: 30045733

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Project description:BACKGROUND:The presynaptic protein neuregulin1 (NRG1) is cleaved by beta-site APP cleaving enzyme 1 (BACE1) in a similar way as amyloid precursor protein (APP) NRG1 can activate post-synaptic receptor tyrosine-protein kinase erbB4 (ErbB4) and was linked to schizophrenia. The NRG1/ErbB4 complex is neuroprotective, can trigger synaptogenesis and plasticity, increases the expression of NMDA and GABA receptors, and can induce neuroinflammation. This complex can reduce memory formation. In Alzheimer's disease (AD) brains, NRG1 accumulates in neuritic plaques. It is difficult to determine if NRG1 has beneficial and/or detrimental effects in AD. BACE1 levels are increased in AD brains and cerebrospinal fluid (CSF) and may lead to enhanced NRG1 secretion, but no study has assessed CSF NRG1 levels in AD and mild cognitive impairment (MCI) patients. METHODS:This retrospective study included 162 patients suffering from AD dementia (54), MCI with progression to AD dementia (MCI-AD) (27), non-AD MCI (30), non-AD dementias (30), and neurological controls (27). All patients had neurological examinations, brain MRI, and neuropsychological evaluations. After written informed consent and using enzyme-linked immunosorbent assays (ELISAs), CSF samples were evaluated for A?1-42, A?1-40, total tau (T-tau), phosphorylated tau on threonine 181 (P-tau), BACE1, growth-associated protein 43 (GAP 43), neurogranin (Ng), and NRG1. RESULTS:Levels of NRG1 were significantly increased in the CSF of AD (+?36%) and MCI-AD (+?28%) patients compared to neurological controls and also non-AD MCI and non-AD dementias. In addition, in AD and MCI-AD patients, NRG1 levels positively correlated with A?1-42 but not with T-tau, P-tau, and BACE1 levels and negatively correlated with MMSE scores. A longitudinal follow-up study of AD patients revealed a trend (p?=?0.08) between CSF NRG1 levels and cognitive decline. In the overall population, NRG1 correlated with MMSE and the synaptic biomarkers GAP 43 and neurogranin. CONCLUSIONS:Our results showed that CSF NRG1 levels are increased in AD and MCI-AD as compared to controls and other dementias. CSF NRG1 levels are associated with cognitive evolution, and a major outcome of our findings is that synaptic NRG1 could be involved in the pathophysiology of AD. Modulating brain NRG1 activity may represent a new therapeutic target in AD.

Dataset Information

Levels of ADAM10 are reduced in Alzheimer's disease CSF.

Background

Methods

Results

Conclusions

Publications

Levels of ADAM10 are reduced in Alzheimer's disease CSF.

Similar Datasets

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