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

Petrus J W Naudé, C. 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

79 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-β-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
JournalFASEB Journal
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2012

Fingerprint

Lipocalins
Tumor Necrosis Factor Receptors
Alzheimer Disease
Neurons
Brain
Lipocalin-2
Microglia
Pathology
Amyloid
Astrocytes
Toxicity
Genes
Tissue
Cytokines
Antibodies

Keywords

  • Mild cognitive impairment
  • Neurodegeneration
  • TNF-α

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Naudé, P. J. W., Nyakas, C., Eiden, L. E., Ait-Ali, D., Van Der Heide, R., Engelborghs, S., ... Eisel, U. L. M. (2012). Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease. FASEB Journal, 26(7), 2811-2823. https://doi.org/10.1096/fj.11-202457

Lipocalin 2 : Novel component of proinflammatory signaling in Alzheimer's disease. / Naudé, Petrus J W; Nyakas, C.; Eiden, Lee E.; Ait-Ali, Djida; Van Der Heide, Ragna; Engelborghs, Sebastiaan; Luiten, Paul G M; De Deyn, Peter P.; Den Boer, Johan A.; Eisel, Ulrich L M.

In: FASEB Journal, Vol. 26, No. 7, 07.2012, p. 2811-2823.

Research output: Contribution to journalArticle

Naudé, PJW, Nyakas, C, Eiden, LE, Ait-Ali, D, Van Der Heide, R, Engelborghs, S, Luiten, PGM, De Deyn, PP, Den Boer, JA & Eisel, ULM 2012, 'Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease', FASEB Journal, vol. 26, no. 7, pp. 2811-2823. https://doi.org/10.1096/fj.11-202457
Naudé PJW, Nyakas C, Eiden LE, Ait-Ali D, Van Der Heide R, Engelborghs S et al. Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease. FASEB Journal. 2012 Jul;26(7):2811-2823. https://doi.org/10.1096/fj.11-202457
Naudé, Petrus J W ; Nyakas, C. ; Eiden, Lee E. ; Ait-Ali, Djida ; Van Der Heide, Ragna ; Engelborghs, Sebastiaan ; Luiten, Paul G M ; De Deyn, Peter P. ; Den Boer, Johan A. ; Eisel, Ulrich L M. / Lipocalin 2 : Novel component of proinflammatory signaling in Alzheimer's disease. In: FASEB Journal. 2012 ; Vol. 26, No. 7. pp. 2811-2823.
@article{07450b58cdd94c19ae3a44042b4c29b1,
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-β-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.",
keywords = "Mild cognitive impairment, Neurodegeneration, TNF-α",
author = "Naud{\'e}, {Petrus J W} and C. Nyakas and Eiden, {Lee E.} and Djida Ait-Ali and {Van Der Heide}, Ragna and Sebastiaan Engelborghs and Luiten, {Paul G M} and {De Deyn}, {Peter P.} and {Den Boer}, {Johan A.} and Eisel, {Ulrich L M}",
year = "2012",
month = "7",
doi = "10.1096/fj.11-202457",
language = "English",
volume = "26",
pages = "2811--2823",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "7",

}

TY - JOUR

T1 - Lipocalin 2

T2 - Novel component of proinflammatory signaling in Alzheimer's disease

AU - Naudé, Petrus J W

AU - Nyakas, C.

AU - Eiden, Lee E.

AU - Ait-Ali, Djida

AU - Van Der Heide, Ragna

AU - Engelborghs, Sebastiaan

AU - Luiten, Paul G M

AU - De Deyn, Peter P.

AU - Den Boer, Johan A.

AU - Eisel, Ulrich L M

PY - 2012/7

Y1 - 2012/7

N2 - 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-β-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

AB - 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-β-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

KW - Mild cognitive impairment

KW - Neurodegeneration

KW - TNF-α

UR - http://www.scopus.com/inward/record.url?scp=84863211375&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863211375&partnerID=8YFLogxK

U2 - 10.1096/fj.11-202457

DO - 10.1096/fj.11-202457

M3 - Article

C2 - 22441986

AN - SCOPUS:84863211375

VL - 26

SP - 2811

EP - 2823

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 7

ER -