학술논문

Glycoprotein NMB: a novel Alzheimer's disease associated marker expressed in a subset of activated microglia
Document Type
Academic Journal
Source
Acta Neuropathologica Communications. October 19, 2018, Vol. 6 Issue 1
Subject
Genetic engineering -- Analysis
Enzyme-linked immunosorbent assay -- Analysis
Melanoma -- Analysis
Advertising executives -- Analysis
Alzheimer's disease -- Analysis
Neurons -- Analysis
Language
English
ISSN
2051-5960
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 A[beta] 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. Keywords: Alzheimer's disease (AD), Glycoprotein nonmetastatic melanoma protein B (GPNMB), Neuroinflammation, Activated microglia, Sporadic AD patients, Transgenic mice, 5XFAD
Author(s): Melanie Hüttenrauch[sup.1] , Isabella Ogorek[sup.2] , Hans Klafki[sup.1] , Markus Otto[sup.3] , Christine Stadelmann[sup.4] , Sascha Weggen[sup.2] , Jens Wiltfang[sup.1,5] and Oliver Wirths[sup.1] Introduction Alzheimer's disease (AD) is a [...]