Title

Retinoic Acid Hydroxylase Inhibitors as a Novel Therapy for Alzheimer’s Disease

Presentation Type

Presentation

Abstract

Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative diseases afflicting the modern world. As no cure for AD has yet been discovered we sought to explore a potential treatment option based on the inhibition of retinoic acid (RA) metabolism, the active metabolite of vitamin A. Beta-amyloid plaques form in the brain and decrease cognitive function in AD patients. In a recent preclinical study RA was shown to decrease these plaques and rescue memory deficits in an Alzheimer’s mouse model (Ding et al. 2008). However, in the human body RA is quickly cleared away by an enzyme, resulting in a loss of activity during long-term treatment. We hypothesize that the inhibition of the enzyme that clears RA would cause an increase in the amount of RA present in the brain. This increased amount of RA would decrease plaques, thereby improving AD patient outcomes. Using two behavioral maze tests, the Morris Water Maze (MWM) and Y maze, we assessed cognitive function based on how quickly the mice maneuvered the mazes. We have begun preclinical testing of the prototypical enzyme inhibitor in Alzheimer’s mice relative to wild type (WT) litter-mates. A MWM measure of latency to the end of the maze showed a discrepancy between the performances of AD and WT mice, with the AD mice exhibiting a considerable cognitive deficit. The mice then received 8 weeks of treatment with the enzyme inhibitor (3 times per week at 10 mg/kg i.p.). A follow-up MWM was performed and no significant reversal of cognitive deficits in AD mice was detected. A more recent MWM study of 31 treated AD mice is currently being analyzed and shows promising similarities between AD and WT latencies. These results provide a strong foundation from which to further explore the use of these inhibitors in treating AD.

Category

Life Sciences

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Retinoic Acid Hydroxylase Inhibitors as a Novel Therapy for Alzheimer’s Disease

UC 330

Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative diseases afflicting the modern world. As no cure for AD has yet been discovered we sought to explore a potential treatment option based on the inhibition of retinoic acid (RA) metabolism, the active metabolite of vitamin A. Beta-amyloid plaques form in the brain and decrease cognitive function in AD patients. In a recent preclinical study RA was shown to decrease these plaques and rescue memory deficits in an Alzheimer’s mouse model (Ding et al. 2008). However, in the human body RA is quickly cleared away by an enzyme, resulting in a loss of activity during long-term treatment. We hypothesize that the inhibition of the enzyme that clears RA would cause an increase in the amount of RA present in the brain. This increased amount of RA would decrease plaques, thereby improving AD patient outcomes. Using two behavioral maze tests, the Morris Water Maze (MWM) and Y maze, we assessed cognitive function based on how quickly the mice maneuvered the mazes. We have begun preclinical testing of the prototypical enzyme inhibitor in Alzheimer’s mice relative to wild type (WT) litter-mates. A MWM measure of latency to the end of the maze showed a discrepancy between the performances of AD and WT mice, with the AD mice exhibiting a considerable cognitive deficit. The mice then received 8 weeks of treatment with the enzyme inhibitor (3 times per week at 10 mg/kg i.p.). A follow-up MWM was performed and no significant reversal of cognitive deficits in AD mice was detected. A more recent MWM study of 31 treated AD mice is currently being analyzed and shows promising similarities between AD and WT latencies. These results provide a strong foundation from which to further explore the use of these inhibitors in treating AD.