Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration

J Neurosci. 2005 Oct 5;25(40):9275-84. doi: 10.1523/JNEUROSCI.2614-05.2005.

Abstract

The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are "primed" to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1beta (IL-1beta) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1beta. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • C-Reactive Protein / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cell Count / methods
  • Cell Death / drug effects*
  • Chronic Disease
  • Cytokines / metabolism
  • Disease Models, Animal
  • Drug Administration Routes
  • Endotoxins / administration & dosage
  • Endotoxins / toxicity*
  • Female
  • Gene Expression Regulation / drug effects
  • Immunohistochemistry / methods
  • In Situ Nick-End Labeling / methods
  • Inflammation / chemically induced
  • Inflammation / physiopathology
  • Interleukin-1 / metabolism
  • Lipopolysaccharides / administration & dosage*
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Neurodegenerative Diseases / pathology*
  • Neurofilament Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / pathology
  • Neutrophil Infiltration / drug effects
  • Neutrophil Infiltration / physiology
  • Phosphopyruvate Hydratase / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Serum Amyloid P-Component / metabolism
  • Signal Transduction / drug effects

Substances

  • Cytokines
  • Endotoxins
  • Interleukin-1
  • Lipopolysaccharides
  • Neurofilament Proteins
  • RNA, Messenger
  • Serum Amyloid P-Component
  • neurofilament protein H
  • PTX3 protein
  • C-Reactive Protein
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Phosphopyruvate Hydratase