title: Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.
authors.affiliation: Department of Molecular Neurobiology, University of Groningen, Groningen, The Netherlands.
authors.forename: Petrus J W
authors.initials: PJ
authors.lastname: Naudé
authors.forename: Csaba
authors.initials: C
authors.lastname: Nyakas
authors.forename: Lee E
authors.initials: LE
authors.lastname: Eiden
authors.forename: Djida
authors.initials: D
authors.lastname: Ait-Ali
authors.forename: Ragna
authors.initials: R
authors.lastname: van der Heide
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Paul G M
authors.initials: PG
authors.lastname: Luiten
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Johan A
authors.initials: JA
authors.lastname: den Boer
authors.forename: Ulrich L M
authors.initials: UL
authors.lastname: Eisel
mesh_terms: D000209:Acute-Phase Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D018836:Inflammation Mediators / Q000134:cerebrospinal fluid / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000819:agonists; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000209:Acute-Phase Proteins; D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D018698:Glutamic Acid