Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0612-3) contains supplementary material, which is available to authorized users.

Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease

“…CD11c + microglia in APP/PS1 mice express high levels of GPNMB (30). Importantly, a subpopulation of Iba1-positive microglia that cluster around amyloid plaques expresses high levels of GPNMB in AD brains (20), consistent with our results.…”

“…DAM is activated sequentially by TREM2-independent and TREM2-dependent pathways. GPNMB reflects a microglia activation state only present under neurodegenerative conditions, which is characterized by upregulation of a subset of genes, including TREM2, APOE, CLEC7A and CST7 (20,31,32). We validated an enhanced expression of GPNMB on amoeboid and hypertrophic microglia accumulating in the frontal white matter of NHD brains and the frontal cortex of AD brains.…”

“…GPNMB is greatly expressed in motor neurons with extracellular deposits in the spinal cord of amyotrophic lateral sclerosis (ALS) (18,19). A subpopulation of Iba1-positive microglia that cluster around amyloid plaques expresses high levels of GPNMB in Alzheimer's disease brains (20). Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by loss-of-function mutations of either TYROBP (DAP12) or TREM2 (21).…”

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…It is highly relevant to note that GPNMB has a neuroprotective role for TDP43 toxicity or ALS [127, 199]. GPNMB was also described as neurodegeneration biomarker in Alzheimer’s, Parkinson’s, Gaucher’s disease and PLOSL leukodystrophy [79, 82, 124, 126, 173].…”

Multi-disease associated risk locus inIL6represses the anti-inflammatory geneGPNMBthrough chromatin looping and recruiting MEF2-HDAC complex

“…Based on our data, the A allele in rs2069837 is associated with suppression of GPNMB expression, which is consistent with the findings that GPNMB expression is increased in Alzheimer's disease, cancer, and infections (36). GPNMB weakens the immune response against cancer cells and infections, contributing to cancer development or chronic infections (37)(38)(39). Since GPNMB has been implicated in multiple tumors, our data discovering genetic regulation of GPNMB by rs2069837 via MEF2-HDAC complex also shed light on mechanisms that can be potentially targeted in malignant disorders.…”