The Alzheimer's disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway.
Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are genetically linked to Alzheimer's disease. Here, we investigated whether human ApoE mediates signal transduction through human and murine TREM2 and sought to identify a TREM2-binding domain in human ApoE.



To investigate cell signaling through TREM2, a cell line was used which expressed an NFAT-inducible β-galactosidase reporter and human or murine TREM2, fused to CD8 transmembrane and CD3ζ intracellular signaling domains. ELISA-based binding assays were used to determine binding affinities of human ApoE isoforms to human TREM2 and to identify a TREM2-binding domain in ApoE.



ApoE was found to be an agonist to human TREM2 with EC50in the low nM range, and to murine TREM2 with reduced potency. In the reporter cells, TREM2 expression was lower than in nontransgenic mouse brain. Human ApoE isoforms ε2, ε3, and ε4 bound to human TREM2 with Kdin the low nM range. The binding was displaced by an ApoE-mimetic peptide (amino acids 130-149).



An ApoE-mediated dose-dependent signal transduction through TREM2 in reporter cells was demonstrated, and a TREM2-binding region in ApoE was identified. The relevance of an ApoE-TREM2 receptor signaling pathway to Alzheimer's disease is discussed.
Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316, Oslo, Norway.
Charlotte
C
Jendresen
Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316, Oslo, Norway.
Vibeke
V
Årskog
Division of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Michael R
MR
Daws
Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316, Oslo, Norway. lars.nilsson@medisin.uio.no.
Lars N G
0000-0002-8362-1042
LN
Nilsson
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002461:Cell Line, Transformed; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008958:Models, Molecular; D040081:Protein Array Analysis; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
Alzheimer’s disease; Apolipoprotein E (ApoE); Neuroinflammation; Reporter cells; Triggering receptor expressed on myeloid cells 2 (TREM2)