RETINOIC ACID HYDROXYLASE INHIBITORS AS A NOVEL THERAPY FOR ALZHEIMER’S DISEASE

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[i]. One key limitation is that when RA is administered to humans it induces its own breakdown, making it less effective for long-term treatment. The proteins mediating RA breakdown are named CYP26. Of the CYP26 enzymes identified as clearing RA, CYP26B1 appears to be the predominant brain isoform. We hypothesize that the inhibition of CYP26 would cause an increase in the amount of RA concentration in the brain, 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 CYP26 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 first selected CYP26 inhibitor NMP300 (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. Furthermore, the stained brain tissues of these mice show a decrease in Beta-Amyloid plaques in AD mice that have received treatment. These results provide a strong foundation from which to further explore the use of these CYP26 inhibitors in treating AD. [i] Ding Y, Qiao A, Wang Z, Goodwin JS, Lee E‐S, Block ML, Allsbrook M, McDonald MP, Fan G‐H. Retinoic Acid Attenuates ß‐Amyloid Deposition and Rescues Memory Deficits in an Alzheimer\u27s Disease Transgenic Mouse Model. The Journal of Neuroscience. 2008;28(45):11622‐34