University of Pittsburgh research demonstrates that bexarotene improves cognitive deficits in mice.
(BHL) - An anti-cancer drug reverses memory deficits in an Alzheimer’s disease mouse model, according to University of Pittsburgh Graduate School of Public Health researchers. Their research reviewed previously published findings on the drug bexarotene, approved by the U.S. Food and Drug Administration for use in cutaneous T-cell lymphoma. The researchers were able to verify that the drug does significantly improve cognitive deficits in mice linked to human Alzheimer’s disease, but could not confirm the effect on amyloid plaques.
“We believe these findings make a solid case for continued exploration of bexarotene as a therapeutic treatment for Alzheimer’s disease,” said senior author Rada Koldamova, M.D., Ph.D., associate professor in University of Pittsburgh's Public Health Department of Environmental and Occupational Health.
Bexarotene is a compound chemically related to vitamin A that activates Retinoic X Receptors (RXR) found everywhere in the body, including neurons and other brain cells. Once activated, the receptors bind to DNA and regulate the expression of genes that control a variety of biological processes. Increased levels of APOE are one consequence of RXR activation by bexarotene.
“We were already set up to repeat a recent Case Western Reserve University study to see if we could independently arrive at the same findings,” said co-author Iliya Lefterov, M.D., Ph.D., associate professor at the University of Pittsburgh. “While we were able to verify that the mice quickly regained their lost cognitive skills and confirmed the decrease in amyloid beta peptides in the interstitial fluid that surrounds brain cells, we did not find any evidence that the drug cleared the plaques from their brains.”
The Pitt researchers postulate that the drug works through a different biological process, perhaps by reducing soluble oligomers which, like the plaques, are composed of the toxic amyloid beta protein fragments. However, the oligomers are composed of smaller amounts of amyloid beta and, unlike the plaques, are still able to “move.”
In the Pitt experiments, mice with the Alzheimer’s gene mutations expressing human APOE3 or APOE4 were able to perform as well in cognitive tests as their non-Alzheimer’s counterparts 10 days after beginning treatment with bexarotene. These tests included a spatial test using cues to find a hidden platform in a water maze and a long-term memory test of the mouse’s ability to discriminate two familiar objects following introduction of a third, novel object.
Bexarotene treatment did not affect the weight or general behavior of the mice. The drug was equally effective in male and female mice.
