An anti-cancer drug may reverse memory problems in an Alzheimer’s Disease mouse model, according to new research carried out at the University of Pittsburgh Graduate School of Public Health.
The study, published in the journal Science, examined previously published outcomes on the drug bexarotene – which is approved by the U.S. Food and Drug Administration for use in cutaneous T cell lymphoma.
The researchers established that the drug does notably improve cognitive deficits in mice expressing gene mutations associated with human Alzheimer’s disease, however, they could not verify the effect on amyloid plaques.
Four comments in the journal Science mention that several teams of scientists have been unable to replicate the medication’s (bexarotene’s) effect on amyloid plaques.
Senior author Rada Koldamova, M.D., Ph.D., associate professor in Pitt Public Health’s Department of Environmental and Occupational Health, said, “We believe these findings make a solid case for continued exploration of bexarotene as a therapeutic treatment for Alzheimer’s disease.”
Dr. Koldamova and her team were studying mice expressing human Apolipoprotein E4 (APOE4) – the only known genetic risk factor for late-onset Alzheimer’s disease, or APOE3 – known not to raise the risk for Alzheimer’s disease – when a Case Western Reserve University study was published last year.
It claimed that bexarotene elevates memory and rapidly cleared amyloid plaques from the brains of Alzheimer’s model mice expressing mouse Apolipoprotein E (APOE).
Amyloid plaques are made up of toxic protein fragments known as amyloid beta that are known to damage neurons in the brain and are believed to result in the memory deficits linked to Alzheimer’s disease, and eventually death.
Bexarotene is a compound chemically associated with vitamin A that triggers Retinoic X Receptors (RXR) found all over the body including neurons and other brain cells. Once they are activated, the receptors bind to DNA and control the expression of genes that guide many different biological functions.
Elevated levels of APOE are one result of RXR activations by bexarotene. The researchers started examining similar compounds over 10 years ago.
Co-author Iliya Lefterov, M.D., Ph.D., associate professor in Pitt Public Health’s Department of Environmental and Occupational Health said:
“We were already set up to repeat the Case Western Reserve University study to see if we could independently arrive at the same findings. 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 investigators believe that the drug functions through a different biological process, possibly by decreasing soluble oligomers which, like the plaques, are made up of the toxic amyloid beta protein pieces. Even though the oligomers are made up of amyloid beta they are able to move, unlike the plaques.
Dr. Koldamova explained:
“We did find a significant decrease in soluble oligomers. It is possible that the oligomers are more dangerous than the plaques in people with Alzheimer’s disease. It also is possible that the improvement of cognitive skills in mice treated with bexarotene is unrelated to amyloid beta and the drug works through a completely different, unknown mechanism.”
In the current study experiments, mice with the Alzheimer’s gene mutations expressing human APOE3 or APOE4 were able to complete cognitive tests just as well as their non-Alzheimer’s counterparts 10 days after starting treatment with bexarotene.
The mice underwent a spatial test that used cues to detect a hidden platform in a water maze, and a long-term memory test of the mouse’s skills in distinguishing between two familiar objects following introduction to a third, new object.
Bexarotene treatment has no impact on the weight or general behavior of the mice. The drug was was successful in both male and female mice.
Written by Kelly Fitzgerald