Glycoprotein NMB: a novel Alzheimer\u2019s disease associated marker expressed in a subset of activated microglia

Melanie Hüttenrauch,Jens Wiltfang,Christine Stadelmann,Isabella Ogorek,Hans Klafki,Oliver Wirths,Markus Otto,Sascha Weggen

doi:10.1186/s40478-018-0612-3

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.

Highlights

Alzheimer’s disease (AD) is a progressive, age-associated neurodegenerative disorder and the most frequent cause of dementia among the elderly population
Glycoprotein nonmetastatic melanoma protein B (GPNMB) expression levels increase with disease progression in distinct transgenic AD mouse models As previously reported, we initially found GPNMB mRNA levels to be significantly up-regulated in 6-month-old APP/PS1KI mice when compared to control mice in a whole-brain deep sequencing analysis [51]
In order to test whether GPNMB mRNA up-regulation occurs during normal aging or if GPNMB expression is regulated in a disease-state dependent manner, RNA of whole brain hemispheres from 3, 7- and 10-month-old APP/PS1KI and PS1KI control mice was extracted and GPNMB expression levels were analyzed using RT-PCR

Summary

Introduction

Alzheimer’s disease (AD) is a progressive, age-associated neurodegenerative disorder and the most frequent cause of dementia among the elderly population. Emerging evidence suggests that instead of solely being a passive response to aberrant protein aggregation in the brain, persistent neuroinflammation might play a causal role in the Hüttenrauch et al Acta Neuropathologica Communications (2018) 6:108 pathogenesis of AD. This hypothesis is supported by recent genome-wide association studies (GWAS) linking specific polymorphisms in inflammation-associated genes such as complement receptor-1 (CR1) [26], CD33 [13, 31] or triggering receptor expressed on myeloid cells-2 (TREM2) [8] to an increased risk for AD. A detailed understanding of immunological processes associated with the disease has become a major goal in Alzheimer’s research in order to evaluate modulation of neuroinflammation as a new therapeutic modality

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