Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia
Open accessAbstract
Alzheimer's disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements. We show that GPNMB levels increase in an age-dependent manner in transgenic AD models showing profound cerebral neuron loss and demonstrate that GPNMB co-localizes with a distinct population of IBA1-positive microglia cells that cluster around amyloid plaques. Our data further indicate that GPNMB is part of a microglia activation state that is only present under neurodegenerative conditions and that is characterized by the up-regulation of a subset of genes including TREM2, APOE and CST7. In agreement, we provide in vitro evidence that soluble Aβ has a direct effect on GPNMB expression in an immortalized microglia cell line. Importantly, we show for the first time that GPNMB is elevated in brain samples and cerebrospinal fluid (CSF) of sporadic AD patients when compared to non-demented controls.The current findings indicate that GPNMB represents a novel disease-associated marker that appears to play a role in the neuroinflammatory response of AD.
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Four proteins (GPNMB, SMOC1, NPTX2, VGF) were previously reported in AD CSF.
“In the list, 4 proteins (GPNMB, SMOC1, NPTX2 and VGF) have previously been reported in AD CSF (Dayon et al., 2018; Huttenrauch et al., 2018; Llano et al., 2019; Xiao et al., 2017)”
From Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression (2020) · cites this paper as Huttenrauch et al., 2018
SMOC1 and GPNMB have been reported as putative CSF biomarkers in previous studies.
“While, SMOC1 and GPNMB have been reported as putative CSF biomarkers in previous studies [18, 33, 62]”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [62]
SMOC1 and GPNMB were reported to be CSF biomarker candidates for Alzheimer's disease in other recent biomarker studies.
“Consistently, SMOC1 and GPNMB were reported to be CSF biomarker candidates for AD in other recent biomarker studies [62, 69].”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [62]
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Cueto, A. F., Álvarez, L., García, M., Artime, E., Álvarez-Barrios, A., Uña, I. R., Coca‐Prados, M., & González‐Iglesias, H. (2020) · Diagnostics · doi:10.3390/diagnostics10060425 · Cited by 4 · see citing works
- Authors
- Hüttenrauch, M., Ogorek, I., Klafki, H., Otto, M., Stadelmann, C., Weggen, S., Wiltfang, J., & Wirths, O.
- Affiliations
- Universitätsmedizin Göttingen (DE)
- Heinrich Heine University Düsseldorf (DE)
- Universität Ulm (DE)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Wirths, Oliver
- Venue
- Acta Neuropathologica Communications
- Published
- 2018-10-19
- Volume
- 6
- Issue
- 1
- Pages
- 108-108
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC6194687
- OpenAlex
- W2898010909
- Cited by
- 166
- References
- 64
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 27 · 2023: 22 · 2022: 15 · 2021: 34 · 2020: 12 · 2019: 8 · 2018: 1 · 2017: 2
- FWCI
- 6.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- Funders
- Alzheimer Forschung Initiative (16013)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- GPNMB, Alzheimer's disease, microglial activation, disease biomarkers, amyloid plaques, TREM2, apolipoprotein E, cystatin F, amyloid-beta, neuroinflammation, cerebrospinal fluid, transgenic mouse model, sporadic Alzheimer's disease
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cell Line, Transformed, Disease Models, Animal, Female, Glial Fibrillary Acidic Protein, Humans, Lipopolysaccharides, Male, Membrane Glycoproteins, Mice, Transgenic, Mutation, Peptide Fragments, Phosphopyruvate Hydratase, Up-Regulation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Presenilin-1
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