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Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease
Author(s) -
Naudé Petrus J. W.,
Nyakas Csaba,
E. Eiden Lee,
AitAli Djida,
Heide Ragna,
Engelborghs Sebastiaan,
Luiten Paul G. M.,
De Deyn Peter P.,
Boer Johan A.,
Eisel Ulrich L. M.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-202457
Subject(s) - proinflammatory cytokine , neuroinflammation , neuroprotection , neurodegeneration , lipocalin , tumor necrosis factor alpha , receptor , microbiology and biotechnology , neuroscience , biology , immunology , medicine , inflammation , endocrinology , disease
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‐a‐mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.—Naudé, P.J. W., Nyakas, C., Eiden, L. E., Ait‐Ali, D., van der Heide, R., Engelborghs, S., Luiten, P. G. M., De Deyn, P. P., den Boer, J. A., Eisel, U. L. M. Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease. FASEB J. 26, 2811–2823 (2012). www.fasebj.org