Abstract
BackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder associated with extracellular amyloid-β peptide deposition and progressive neuron loss. Strong evidence supports that neuroinflammatory changes such as the activation of astrocytes and microglia cells are important in the disease process. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that has recently been associated with an emerging role in neuroinflammation, which has been reported to be increased in post-mortem brain samples from AD and Parkinson’s disease patients.MethodsThe present study describes the partial “fit for purpose” validation of a commercially available immunoassay for the determination of GPNMB levels in the cerebrospinal fluid (CSF). We further assessed the applicability of GPNMB as a potential biomarker for AD in two different cohorts that were defined by biomarker-supported clinical diagnosis or by neuroimaging with amyloid positron emission tomography, respectively.ResultsThe results indicated that CSF GPNMB levels could not distinguish between AD or controls with other neurological diseases but correlated with other parameters such as aging and CSF pTau levels.ConclusionsThe findings of this study do not support GPNMB in CSF as a valuable neurochemical diagnostic biomarker of AD but warrant further studies employing healthy control individuals.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative disorder with a high demand for care that is putting an enormous strain on global healthcare systems
To confirm the successful GPNMBknockout, THP-1 cells were differentiated to adherent macrophage-like cells by treatment with phorbol myristate acetate (PMA), and RNA was extracted and reverse-transcribed into Complementary DNA (cDNA) from control cells transduced with a guide RNA targeting enhanced green fluorescent protein (EGFP), as well as from two individual cell clones transduced with guide RNAs targeting two distinct sequences in exon 2 of the human Glycoprotein nonmetastatic melanoma protein B (GPNMB) gene (GPNMB Ex2.1, clone R; GPNMB Ex2.2 clone B)
Conditioned cell supernatants and cellular lysates were collected from THP-1 derived macrophages and GPNMB protein levels were measured with the osteoactivin R-PLEX assay
Summary
Alzheimer’s disease (AD) is a common neurodegenerative disorder with a high demand for care that is putting an enormous strain on global healthcare systems. The two neuropathological hallmark lesions comprise extracellular amyloid-β (Aβ) plaques and Aichholzer et al Alzheimer's Research & Therapy (2021) 13:94 ratio in combination with increased levels of total Tau (tTau) and phosphorylated Tau (pTau) proteins represent accepted biomarkers supporting the diagnosis of AD dementia [6,7,8]. In recent years, neuroimaging tools for in vivo amyloid detection by positron emission tomography (PET) using tracers such as 11C-Pittburgh compound B, 18F-florbetaben, or 18F-flutemetamol became available, showing good inverse correlations with CSF Aβ42 levels [9,10,11]. Alzheimer’s disease (AD) is a neurodegenerative disorder associated with extracellular amyloid-β peptide deposition and progressive neuron loss. We further assessed the applicability of GPNMB as a potential biomarker for AD in two different cohorts that were defined by biomarker-supported clinical diagnosis or by neuroimaging with amyloid positron emission tomography, respectively
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