Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

J Neuroinflammation. 2008 Aug 29;5:37. doi: 10.1186/1742-2094-5-37.

Abstract

Background: Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Abeta) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD.

Methods: In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting.

Results: Intraperitoneal injection of LPS, (250 microg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 microg/kg, 3 or 7 times) resulted in an accumulation of Abeta1-42 in the hippocampus and cerebralcortex of mice brains through increased beta- and gamma-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Abeta1-42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5-50 microM) also suppressed LPS (1 microg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro.

Conclusion: This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / immunology
  • Alzheimer Disease* / pathology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Behavior, Animal / physiology
  • Brain / anatomy & histology
  • Brain / immunology*
  • Brain / pathology
  • Cells, Cultured
  • Cognition Disorders / immunology*
  • Female
  • Humans
  • Inflammation / immunology*
  • Isoenzymes / metabolism
  • Learning / physiology
  • Lipopolysaccharides / immunology*
  • Male
  • Memory Disorders / immunology
  • Mice
  • Neurons / cytology
  • Neurons / metabolism
  • Pregnancy
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Sulindac / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Anti-Inflammatory Agents, Non-Steroidal
  • Isoenzymes
  • Lipopolysaccharides
  • Sulindac
  • Amyloid Precursor Protein Secretases