| First Author | Chu J | Year | 2011 |
| Journal | Am J Pathol | Volume | 178 |
| Issue | 4 | Pages | 1762-9 |
| PubMed ID | 21435457 | Mgi Jnum | J:169845 |
| Mgi Id | MGI:4943348 | Doi | 10.1016/j.ajpath.2010.12.032 |
| Citation | Chu J, et al. (2011) Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an Alzheimer's Disease Transgenic Mouse Model Involvement of gamma-Secretase. Am J Pathol 178(4):1762-9 |
| abstractText | The 5-lipoxygenase (5-LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD) and that its genetic absence results in a reduction of amyloid beta (Abeta) levels in Tg2576 mice. In the present study, we examined the effect of 5-LO pharmacological inhibition on the amyloidotic phenotype of these mice. Abeta deposition in the brains of mice receiving zileuton, a selective and specific 5-LO inhibitor, was significantly reduced when compared with control Tg2576 mice receiving vehicle. This reduction was associated with a similar decrease in brain Abeta peptides levels. Zileuton treatment did not induce any change in the steady state levels of amyloid-beta precursor protein (APP), BACE1 or ADAM10. By contrast, it resulted in a significant reduction of presenilin 1 (PSEN1, alias PS1), nicastrin (NCSTN) , presenilin enhancer 2 homolog (PSNEN, alias, Pen-2), and anterior pharynx defective 1 (APH-1), the four components of the gamma-secretase complex-at the protein and message level. Furthermore, in vitro studies confirmed that zileuton prevents Abeta formation by modulating gamma-secretase complex levels without affecting Notch signaling. These data establish a functional role for 5-LO in the pathogenesis of AD-like amyloidosis, whereby it modulates the gamma-secretase pathway. They suggest that pharmacological inhibition of 5-LO could provide a novel therapeutic opportunity for AD. |
