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Identification of small molecule inhibitors of neurite loss induced by A? peptide using high content screening.

ABSTRACT: Multiple lines of evidence indicate a strong relationship between ?? 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 A? 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 A?-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 A? treatment. Furthermore, multiple distinct classes of COX inhibitors efficiently blocked neurite loss in primary neurons, suggesting that increased COX activity contributes to A? 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 ? (PPAR?) activity. Overall, our work establishes the feasibility of identifying small molecule inhibitors of A?-induced neurite loss using the NeuriteIQ pipeline and provides novel insights into the mechanisms of neuroprotection by NSAIDs.

SUBMITTER: Ofengeim D

PROVIDER: S-EPMC3308767 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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

Ofengeim Dimitry D Shi Peng P Miao Benchun B Fan Jing J Xia Xiaofeng X Fan Yubo Y Lipinski Marta M MM Hashimoto Tadafumi T Polydoro Manuela M Yuan Junying J Wong Stephen T C ST Degterev Alexei A

The Journal of biological chemistry 20120125 12

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 represen ...[more]

PMID: 22277654

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Project description:ERBB2 amplification and overexpression are strongly associated with invasive cancer with high recurrence and poor prognosis. Enhanced ErbB2 signaling induces cysteine cathepsin B and L expression leading to their higher proteolytic activity (zFRase activity), which is crucial for the invasion of ErbB2-positive breast cancer cells in vitro. Here we introduce a simple screening system based on zFRase activity as a primary readout and a following robust invasion assay and lysosomal distribution analysis for the identification of compounds that can inhibit ErbB2-induced invasion. With an unbiased kinase inhibitor screen, we identified Bohemine/Roscovitine, Gö6979 and JAK3 inhibitor VI as compounds that can efficiently decrease cysteine cathepsin activity. Using the well-established and clinically relevant ErbB1 and ErbB2 inhibitor lapatinib as a positive control, we studied their ability to inhibit ErbB2-induced invasion in 3-dimensional Matrigel cultures. We found one of them, JAK3 inhibitor VI, capable of inhibiting invasion of highly invasive ErbB2-positive ovarian cancer cells as efficiently as lapatinib, whereas Gö6979 and Roscovitine displayed more modest inhibition. All compounds reversed the malignant, ErbB2-induced and invasion-supporting peripheral distribution of lysosomes. This effect was most evident for lapatinib and JAK3 inhibitor VI and milder for Gö6979 and Roscovitine. Our results further showed that JAK3 inhibitor VI function was independent of JAK kinases but involved downregulation of cathepsin L. We postulate that the screening method and the verification experiments that are based on oncogene-induced changes in lysosomal hydrolase activity and lysosomal distribution could be used for identification of novel inhibitors of ErbB2-induced invasiveness. Additionally, we introduce a novel function for lapatinib in controlling malignant lysosomal distribution, that may also be involved in its capability to inhibit ErbB2-induced invasion in vivo.

Dataset Information

Identification of small molecule inhibitors of neurite loss induced by A? peptide using high content screening.

Publications

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

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