Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease

Petrus J W Naudé, Csaba Nyakas, Lee E Eiden, Djida Ait-Ali, Ragna van der Heide, Sebastiaan Engelborghs, Paul G M Luiten, Peter P De Deyn, Johan A den Boer, Ulrich L M Eisel

Research output: Contribution to journalArticle

99 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2811-2823
Number of pages13
JournalThe FASEB Journal
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • Acute-Phase Proteins/cerebrospinal fluid
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease/cerebrospinal fluid
  • Amyloid beta-Peptides/toxicity
  • Animals
  • Base Sequence
  • Brain/metabolism
  • Case-Control Studies
  • Cells, Cultured
  • Cognitive Dysfunction/cerebrospinal fluid
  • Female
  • Gene Expression/drug effects
  • Glutamic Acid/toxicity
  • Humans
  • Inflammation Mediators/cerebrospinal fluid
  • Lipocalin-2
  • Lipocalins/cerebrospinal fluid
  • Male
  • Mice
  • Models, Neurological
  • Neurons/drug effects
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins/genetics
  • Proto-Oncogene Proteins/cerebrospinal fluid
  • RNA, Messenger/genetics
  • Receptors, Tumor Necrosis Factor, Type I/agonists
  • Receptors, Tumor Necrosis Factor, Type II/agonists
  • Signal Transduction
  • Tumor Necrosis Factor-alpha/metabolism

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