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CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease

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 n...

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Autores principales: Mouton-Liger, François, Dumurgier, Julien, Cognat, Emmanuel, Hourregue, Claire, Zetterberg, Henrik, Vanderstichele, Hugo, Vanmechelen, Eugeen, Bouaziz-Amar, Elodie, Blennow, Kaj, Hugon, Jacques, Paquet, Claire
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372801/
https://www.ncbi.nlm.nih.gov/pubmed/32690068
http://dx.doi.org/10.1186/s13195-020-00655-w
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author Mouton-Liger, François
Dumurgier, Julien
Cognat, Emmanuel
Hourregue, Claire
Zetterberg, Henrik
Vanderstichele, Hugo
Vanmechelen, Eugeen
Bouaziz-Amar, Elodie
Blennow, Kaj
Hugon, Jacques
Paquet, Claire
author_facet Mouton-Liger, François
Dumurgier, Julien
Cognat, Emmanuel
Hourregue, Claire
Zetterberg, Henrik
Vanderstichele, Hugo
Vanmechelen, Eugeen
Bouaziz-Amar, Elodie
Blennow, Kaj
Hugon, Jacques
Paquet, Claire
author_sort Mouton-Liger, François
collection PubMed
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 Aβ1–42, Aβ1–40, 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 Aβ1–42 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.
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spelling pubmed-73728012020-07-21 CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease Mouton-Liger, François Dumurgier, Julien Cognat, Emmanuel Hourregue, Claire Zetterberg, Henrik Vanderstichele, Hugo Vanmechelen, Eugeen Bouaziz-Amar, Elodie Blennow, Kaj Hugon, Jacques Paquet, Claire Alzheimers Res Ther Research 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 Aβ1–42, Aβ1–40, 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 Aβ1–42 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. BioMed Central 2020-07-20 /pmc/articles/PMC7372801/ /pubmed/32690068 http://dx.doi.org/10.1186/s13195-020-00655-w Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Mouton-Liger, François
Dumurgier, Julien
Cognat, Emmanuel
Hourregue, Claire
Zetterberg, Henrik
Vanderstichele, Hugo
Vanmechelen, Eugeen
Bouaziz-Amar, Elodie
Blennow, Kaj
Hugon, Jacques
Paquet, Claire
CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease
title CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease
title_full CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease
title_fullStr CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease
title_full_unstemmed CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease
title_short CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease
title_sort csf levels of the bace1 substrate nrg1 correlate with cognition in alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372801/
https://www.ncbi.nlm.nih.gov/pubmed/32690068
http://dx.doi.org/10.1186/s13195-020-00655-w
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