Identification of small molecule inhibitors of neurite loss induced by Aβ peptide using high content screening

Dimitry Ofengeim, Peng Shi, Benchun Miao, Jing Fan, Ofeng Xia, Yubo Fan, Marta M. Lipinski, Tadafumi Hashimoto, Manuela Polydoro, Junying Yuan, Stephen T.C. Wong, Alexei Degterev

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Multiple lines of evidence indicate a strong relationship between Aβ peptide-induced neurite degeneration and the progressive loss of cognitive functions in Alzheimer disease (AD) patients and in AD animal models. This prompted us to develop a high content screening assay (HCS) and Neurite Image Quantitator (NeuriteIQ) software to quantify the loss of neuronal projections induced by Aβ peptide neurons and enable us to identify new classes of neurite-protective small molecules, which may represent new leads for AD drug discovery. We identified thirty-six inhibitors of Aβ-induced neurite loss in the 1,040-compound National Institute of Neurological Disorders and Stroke (NINDS) custom collection of known bioactives andFDA approved drugs. Activity clustering showed that non-steroidal anti-inflammatory drugs (NSAIDs) were significantly enriched among the hits. Notably, NSAIDs have previously attracted significant attention as potential drugs for AD; however their mechanism of action remains controversial. Our data revealed that cyclooxygenase-2 (COX-2) expression was increased following Aβ treatment. Furthermore, multiple distinct classes of COXinhibitors efficiently blocked neurite loss in primary neurons, suggesting that increased COX activity contributes to Aβ peptide-induced neurite loss. Finally, we discovered that the detrimental effect of COX activity on neurite integrity may be mediated through the inhibition of peroxisome proliferator-activated receptor γ (PPARγ) activity. Overall, our work establishes the feasibility of identifying small molecule inhibitors of Aβ-induced neurite loss using the NeuriteIQ pipeline and provides novel insights into the mechanisms of neuroprotection by NSAIDs.

Original languageEnglish (US)
Pages (from-to)8714-8723
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number12
DOIs
StatePublished - Mar 16 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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