title: Identification of small molecule inhibitors of neurite loss induced by Aβ peptide using high content screening.
abstract: Multiple lines of evidence indicate a strong relationship between Αβ 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 and FDA 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 COX inhibitors 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dimitry
authors.initials: D
authors.lastname: Ofengeim
authors.forename: Peng
authors.initials: P
authors.lastname: Shi
authors.forename: Benchun
authors.initials: B
authors.lastname: Miao
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xia
authors.forename: Yubo
authors.initials: Y
authors.lastname: Fan
authors.forename: Marta M
authors.initials: MM
authors.lastname: Lipinski
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Manuela
authors.initials: M
authors.lastname: Polydoro
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009410:Nerve Degeneration; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D047495:PPAR gamma; D054852:Small Molecule Libraries