Anti-inflammatory drug therapy alters β-amyloid processing and deposition in an animal model of Alzheimer's disease

Qiao Yan, Jianhua Zhang, Hantao Liu, Safura Babu-Khan, Robert Vassar, Anja Leona Biere, Martin Citron*, Gary Landreth

*Corresponding author for this work

Research output: Contribution to journalArticle

422 Scopus citations

Abstract

Alzheimer's disease (AD) is characterized by a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Nonsteroidal anti-inflammatory drug (NSAID) treatment reduces AD risk, slows disease progression, and reduces microglial activation; however, the basis of these effects is unknown. We report that treatment of 11-month-old Tg2576 mice overexpressing human amyloid precursor protein (APP) with the NSAID ibuprofen for 16 weeks resulted in the dramatic and selective reduction of SDS-soluble β-amyloid (Aβ)42, whereas it had smaller effects on SDS-soluble Aβ40 levels. Ibuprofen treatment resulted in 60% reduction of amyloid plaque load in the cortex of these animals. In vitro studies using APP-expressing 293 cells showed that ibuprofen directly affected APP processing, specifically reducing the production of Aβ42. Ibuprofen treatment resulted in a significant reduction in microglial activation in the Tg2576 mice, as measured by CD45 and CD11b expression. NSAIDs activate the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ); however, a potent agonist of this receptor, pioglitazone, only modestly reduced SDS-soluble Aβ levels and did not affect amyloid plaque burden or microglia activation, indicating that PPARγ activation is not involved in the Aβ lowering effect of NSAIDs. These data show that chronic NSAID treatment can reduce brain Aβ levels, amyloid plaque burden, and microglial activation in an animal model of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)7504-7509
Number of pages6
JournalJournal of Neuroscience
Volume23
Issue number20
StatePublished - Aug 20 2003

Keywords

  • β-amyloid
  • Alzheimer's disease
  • Inflammation
  • Microglia
  • NSAIDs
  • PPARγ

ASJC Scopus subject areas

  • Neuroscience(all)

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    Yan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A. L., Citron, M., & Landreth, G. (2003). Anti-inflammatory drug therapy alters β-amyloid processing and deposition in an animal model of Alzheimer's disease. Journal of Neuroscience, 23(20), 7504-7509.