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Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

Kiran Bhaskar1, Nicole Maphis1, Guixiang Xu2

  • 1Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, USA.

Neurobiology of Disease
|October 22, 2013
PubMed

Insights

Microglia-driven neuroinflammation induces toxic neuronal cell cycle events in Alzheimer's disease (AD) via tumor necrosis factor-alpha (TNFα). This identifies TNFα as a key driver of neuronal damage and cell death in AD pathogenesis.

Area of Science:

  • Neuroscience
  • Immunology
  • Pathology

Background:

  • Alzheimer's disease (AD) is characterized by significant neuronal loss.
  • The precise mechanisms driving this neuronal loss remain incompletely understood.
  • Neuroinflammation, particularly microglial activation, is increasingly implicated in AD pathogenesis.

Purpose of the Study:

  • To investigate the role of microglia-mediated neuroinflammation in inducing neuronal cell cycle events (CCEs).
  • To identify the specific molecular pathways and cytokines involved in microglial-induced neuronal toxicity.
  • To determine if these findings translate to the human AD brain.

Main Methods:

  • Utilized oligomeric amyloid-beta peptide (AβO) to activate microglia and assess neuronal CCEs.
  • Investigated the involvement of tumor necrosis factor-alpha (TNFα) and c-Jun Kinase (JNK) signaling pathways.
  • Employed adoptive transfer of microglia from AD transgenic mice and genetic TNFα deficiency models.
  • Examined human AD brain tissue for co-localization of activated microglia and mitotically active, apoptotic neurons.

Main Results:

  • Oligomeric amyloid-beta peptide (AβO)-mediated microglial activation induced neuronal CCEs through TNFα and JNK signaling.
  • Adoptive transfer of AD microglia induced neuronal cyclin D1 expression, dependent on TNFα.
  • Genetic deficiency of TNFα prevented microglial induction of neuronal CCEs in AD mice.
  • Mitotically active, apoptotic neurons were found alongside activated microglia in human AD brains.

Conclusions:

  • Microglia play a cell-autonomous role in promoting neuronal CCEs, which are toxic to terminally differentiated neurons.
  • Tumor necrosis factor-alpha (TNFα) is identified as the key cytokine mediating microglial-induced neuronal CCEs in AD.
  • These findings highlight a novel mechanism contributing to neuronal loss in Alzheimer's disease pathogenesis.
Keywords:
ADAdoptive transferAlzheimer's diseaseAβFAβOBrdUBromodeoxyuridineCCECMCOX2GFPIDVIKKα/βIL-1βIL-6INFγIκB kinase α/βJNKLPSMAP2MicrogliaNOSNSAIDNeuroinflammationNeuronal cell cyclePASPBSPCNAPFAPI3KPhosphatidylinositol 3-kinaseROIRTSTAT3Signal transducer and activator of transcription 3TNF receptorTNFRTNFαTUNELTerminal deoxynucleotidyl transferase dUTP nick end labelingTumor Necrosis Factor-αTumor necrosis factor-α (TNFα)c-Jun Kinasec-Jun Kinase (JNK)cell cycle eventsconditioned mediacyclooxygenase-2fibrillar amyloid-beta peptidegreen fluorescent proteinintegrated density valueinterferon-γinterleukin-1βinterleukin-6lipopolysaccharidemicrotubule associated protein-2nitric oxide synthasenon-steroidal anti-inflammatory drugoligomeric amyloid-beta peptidep38 MAPKp38 mitogen activated protein kinaseparaformaldehydephosphate buffered salineproliferating cell nuclear antigenprotein-A-sepharoseregion of interestroom temperature

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