Intramembranous processing by γ‐secretase regulates reverse signaling of ephrin‐B2 in migration of microglia

Kemmerling, Nadja; Wunderlich, Patrick; Theil, Sandra; Linnartz‐Gerlach, Bettina; Hersch, Nils; Hoffmann, Bernd; Heneka, Michael T.; Strooper, Bart De; Neumann, Harald; Walter, Jochen

doi:10.1002/glia.23147

Cited by 14 publications

(19 citation statements)

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“…Of note, the areas covered by ramified microglia do not overlap, in comparison with the area covered by astrocytes [ 87 ]. Only little is known about the factors and molecular mechanisms controlling colonisation, migration and settling of the cells, although α5β1 integrin and fibronectins, as well as γ-secretase, seem to play an important role [ 88 , 81 ]. In addition, little is known about the molecular mechanisms of the interaction between microglia and neurons.…”

Section: Introductionmentioning

confidence: 99%

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

et al. 2017

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Microglia cells are the unique residential macrophages of the central nervous system (CNS). They have a special origin, as they derive from the embryonic yolk sac and enter the developing CNS at a very early stage. They play an important role during CNS development and adult homeostasis. They have a major contribution to adult neurogenesis and neuroinflammation. Thus, they participate in the pathogenesis of neurodegenerative diseases and contribute to aging. They play an important role in sustaining and breaking the blood-brain barrier. As innate immune cells, they contribute substantially to the immune response against infectious agents affecting the CNS. They play also a major role in the growth of tumours of the CNS. Microglia are consequently the key cell population linking the nervous and the immune system. This review covers all different aspects of microglia biology and pathology in a comprehensive way.

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Section: Introductionmentioning

confidence: 99%

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

et al. 2017

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“…; Kemmerling et al . ). Impairment of γ‐secretase function results in decreased generation of ICD s and alters signaling of the respective protein substrates.…”

Section: γ‐Secretase and Intramembrane Proteolysismentioning

confidence: 97%

“…Recently, γ‐secretase‐dependent processing of ephrin B2 has been implicated in the regulation of microglial migration (Kemmerling et al . ). Ephrin B2 belongs to the family of ligands for erythropoietin‐producing human hepatocellular (Eph) receptors (Kania and Klein ).…”

Section: Implications Of γ‐Secretase In Microglial Functionmentioning

confidence: 97%

“…In mouse primary and embryonic stem cell‐derived microglia, ephrin B2 undergoes ectodomain shedding by an α‐secretase like activity, and this process is stimulated by the interaction with a recombinant soluble variant of the EphB1 receptor (Kemmerling et al . ). After shedding of the ephrin B2 ectodomain, the remaining ephrin B2 CTF is subjected to γ‐secretase‐mediated cleavage resulting in the release of the ephrin B2 ICD from cellular membranes.…”

Section: Implications Of γ‐Secretase In Microglial Functionmentioning

confidence: 97%

“…Interestingly, these effects are attenuated upon pharmacologic or genetic inhibition of γ‐secretase (Kemmerling et al . ). Inhibition of γ‐secretase also impaired the dynamics of podosomes, and the migration of microglia in culture.…”

Section: Implications Of γ‐Secretase In Microglial Functionmentioning

confidence: 97%

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γ‐Secretase in microglia – implications for neurodegeneration and neuroinflammation

Walter

Kemmerling

Wunderlich

et al. 2017

Journal of Neurochemistry

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c-Secretase is an intramembrane cleaving protease involved in the generation of the Alzheimer's disease (AD)-associated amyloid b peptide (Ab). c-Secretase is ubiquitously expressed in different organs, and also in different cell types of the human brain. Besides the involvement in the proteolytic generation of Ab from the amyloid precursor protein, c-secretase cleaves many additional protein substrates, suggesting pleiotropic functions under physiological and pathophysiological conditions. Microglia exert important functions during brain development and homeostasis in adulthood, and accumulating evidence indicates that microglia and neuroinflammatory processes contribute to the pathogenesis of neurodegenerative diseases. Recent studies demonstrate functional implications of c-secretase in microglia, suggesting that alterations in c-secretase activity could contribute to AD pathogenesis by modulation of microglia and related neuroinflammatory processes during neurodegeneration. In this review, we discuss the involvement of c-secretase in the regulation of microglial functions, and the potential relevance of these processes under physiological and pathophysiological conditions. Keywords: ephrin, microglia, notch, presenilin, proteolytic processing, secretase, TREM2.This article is part of the series "Beyond Amyloid".Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid b plaques and neurofibrillary tangles in the brain (Braak et al. 2011;Hyman et al. 2012). Evidence from neuropathological, genetic, biochemical, and cell biological studies strongly support a critical role of the amyloid b-peptide (Ab) in AD pathogenesis (Selkoe 2001;Selkoe and Hardy 2016). In most of the cases, AD manifests later in life (> 65 years of age). In rare familial forms of AD (FAD), however, characteristic symptoms and pathology occur much earlier (20-65 years of age). Mutations in three different genes are known to be responsible for about half of all FAD cases, and these three genes are directly involved in the generation of Ab (Kennedy et al. Address correspondence and reprint requests to Dr Jochen Walter, Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. E-mail: jochen.walter@ukbonn.deAbbreviations used: AD, Alzheimer's disease; ADAM, a disintegrin and metalloproteinase; Aph-1, anterior pharynx-defective 1; ApoE, apolipoprotein E; APP, amyloid precursor protein; Ab, amyloid b peptide; BACE1, b-site APP cleaving enzyme 1; CD11b, integrin alpha M; CNS, central nervous system; CTF, C-terminal fragment; DAP12/ TYROBP, DNAX-Activation Protein 12 synonym of TYRO Protein Tyrosine Kinase Binding Protein; dKO, double knock-out; Eph, erythropoietin-producing human hepatocellular; FAD, familial Alzheimer's disease; ICD, intracellular domain; IL, interleukin; kDa, kilo Dalton; KO, knock out; LPS, lipopolysaccharide; NICD, notch intracellular domain; pen-2, presenilin enhancer-2; PS, presenilin; RIP, regulated intramembrane proteolysis; sTREM2, soluble TREM2; TNF, tum...

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A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease‐associated variants on receptor signaling and activation by antibodies against the stalk region

Ibach

Mathews

Linnartz‐Gerlach

et al. 2020

Glia

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The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on myeloid‐derived cell types. The extracellular immunoglobulin‐like domain of TREM2 binds anionic ligands including Apolipoprotein E and Amyloid‐β. The transmembrane domain interacts with its adaptor protein DAP12/TYROBP that is responsible for propagation of downstream signaling upon ligand interaction. Several sequence variants of TREM2 have been linked to different neurodegenerative diseases including Alzheimer's disease. Here, we generated HEK 293 Flp‐In cell lines stably expressing human TREM2 and DAP12 using a bicistronic construct with a T2A linker sequence allowing initial expression of both proteins in stoichiometric amounts. Cell biological and biochemical analyses revealed transport of TREM2 to the cell surface, and canonical sequential proteolytic processing and shedding of TREM2 (sTREM2). The functionality of this cell system was demonstrated by detection of phosphorylated spleen tyrosine kinase (SYK) upon stimulation of TREM2 with the anionic membrane lipid phosphatidylserine or anti‐TREM2 antibodies. Using this cell model, we demonstrated impaired signaling of disease associated TREM2 variants. We also identified a monoclonal antibody against the stalk region of TREM2 with agonistic activity. Activation of TREM2‐DAP12 signaling with the monoclonal antibody and the partial loss of function of disease associated variants were recapitulated in induced pluripotent stem cell derived microglia. Thus, this reporter cell model represents a suitable experimental system to investigate signaling of TREM2 variants, and for the identification of ligands and compounds that modulate TREM2‐DAP12 signaling. MAIN POINTS Disease associated variants impair the signaling activity of TREM2 by distinct mechanisms. Targeting the stalk region of TREM2 with bivalent antibodies activates TREM2 signaling.

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Intramembranous processing by γ‐secretase regulates reverse signaling of ephrin‐B2 in migration of microglia

Cited by 14 publications

References 61 publications

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

γ‐Secretase in microglia – implications for neurodegeneration and neuroinflammation

A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease‐associated variants on receptor signaling and activation by antibodies against the stalk region

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