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- Title
Modulation of 5-Lipoxygenase in Proteotoxicity and Alzheimer's Disease.
- Authors
Valera, Elvira; Dargusch, Richard; Maher, Pamela A.; Schubert, David
- Abstract
The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2ɑ/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aɑ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2ɑ and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2ɑ phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. Therefore, 5-LOX metabolism is a key element in the promotion of endoplasmic reticulum dysfunction, and its inhibition under condi-tions of stress is sufficient to reduce proteotoxicity both in vivo and in vitro.
- Subjects
LIPOXYGENASES; ALZHEIMER'S disease diagnosis; PHOSPHORYLATION; PROTEIN kinases; BIOACCUMULATION; CELL death
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 25, p10512
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5183-12.2013