Blocking 5-Lipoxygenase May Prevent Development of Alzheimer's Disease

Inhibition of the enzyme 5-lipoxygenase has been shown to decrease the formation of amyloid beta protein, the major component of plaques implicated in the development of Alzheimer's disease.

The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is especially active in Alzheimer's disease.

Writing in the November 17, 2010, online edition of the journal Annals of Neurology, investigators at Temple University (Philadelphia, PA, USA) reported that 5-LO regulated the formation of amyloid beta by activating the cAMP-response element binding protein (CREB), which in turn increased transcription of the gamma-secretase complex.

Preventing CREB activation with drugs or through genetic manipulation blocked the 5-LO-dependent elevation of amyloid beta formation and the increase of gamma-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its selective inhibition by drug treatment resulted in a significant reduction of amyloid beta, CREB, and gamma-secretase levels.

"What we found was that 5-lipoxygenase regulates and controls the amount of total amyloid beta produced in the brain,” said senior author Dr. Domenico Praticò, associate professor of pharmacology at Temple University. "With aging, the more 5-lipoxygenase you have the more amyloid beta you are going to produce. This will translate into a higher risk to develop full Alzheimer's.”

"It has been known for years that the 5-lipoxygenase is an important protein in other areas of the body, such as the lung, but nobody really cared about its role in the brain,” said Dr. Praticò. "Based on some previously know information, we questioned whether this enzyme was a primary or secondary player in the development of Alzheimer's. What we found was a new primary role for an old enzyme. If you can modulate this enzyme easily, then you can control the amount of total amyloid beta that is produced by the gamma secretase in the brain, thus controlling the amount of Alzheimer's disease.”

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