Background: TREM2 is a microglial receptor, recently identified as a genetic risk factor for late onset AD. Results: Sequential proteolytic processing of TREM2 involves ectodomain shedding and intramembranous cleavage by ␥-secretase and affects signaling via its adaptor protein DAP12. Conclusion: ␥-Secretase-mediated intramembranous proteolysis modulates TREM2 signaling. Significance: Inhibition of ␥-secretase could impair TREM2 function in neuroinflammation.

Edited by Noboru Mizushima

The Eph‐ephrin system plays pivotal roles in cell adhesion and migration. The receptor‐like functions of the ephrin ligands allow the regulation of intracellular processes via reverse signaling. γ‐Secretase mediated processing of ephrin‐B has previously been linked to activation of Src, a kinase crucial for focal adhesion and podosome phosphorylation. Here, we analyzed the role of γ‐secretase in the stimulation of reverse ephrin‐B2 signaling in the migration of mouse embryonic stem cell derived microglia. The proteolytic generation of the ephrin‐B2 intracellular domain (ICD) by γ‐secretase stimulates Src and focal adhesion kinase (FAK). Inhibition of γ‐secretase decreased the phosphorylation of Src and FAK, and reduced cell motility. These effects were associated with enlargement of the podosomal surface. Interestingly, expression of ephrin‐B2 ICD could rescue these effects, indicating that this proteolytic fragment mediates the activation of Src and FAK, and thereby regulates podosomal dynamics in microglial cells. Together, these results identify γ‐secretase as well as ephrin‐B2 as regulators of microglial migration.

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...