A drug approved for the treatment of cancer appears to quickly reverse the symptoms of Alzheimer’s in mice, according to a new study from the US published in the journal Science on Thursday.
The Food and Drug Administration (FDA) approved bexarotene as a treatment for cutaneous T cell lymphoma, a type of skin cancer, in 2000. Now a team of neuroscientists has shown that when they gave the drug to mice with Alzheimer’s disease, it quickly reversed the pathological, cognitive and memory deficits that accompanies it.
About 5.4 million Americans have Alzheimer’s disease, the most common form of dementia. While the cause of the disease is not well understood, studies have shown it is linked to an inability to clear away beta-amyloid plaques that accumulate around brain cells.
The study was conducted in the lab of senior author Dr Gary Landreth, professor of neurosciences at Case Western Reserve University School of Medicine in Cleveland, Ohio.
From previous work, Landreth had already established that the protein Apolipoprotein E (ApoE), the main cholesterol transporter in the brain, also helps to clear away amyloid beta.
So, he and his colleagues decided to see what effect bexarotene might have on this process, since it was already known that one of the effects of the drug is that it stimulates a group of receptors that help control production of ApoE, the retinoid X receptors (RXR).
They were astonished at the results.
Within six hours of administering bexarotene, levels of soluble amyloid levels fell by 25%. And they were even more impressed when they saw the effect lasted for three days, at which point there was more than 50% reduction in amyloid beta plaques. Eventually, the reduction was more than 75%.
And finally, the change in amyloid levels was accompanied by rapid improvement in a range of observable behaviors in the three different types of mouse model of Alzheimer’s that they used:
“… bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function,” write the authors.
One improvement they noticed was in the mice’s nesting behavior. Before receiving bexarotene, the Alzheimer’s-diseased mice did not start to make a space for a nest when they encountered tissue paper. But just 3 days after treatment, they started to use the paper to make nests.
Landreth and colleagues conclude that activating the RXR receptors with bexarotene “stimulates physiological [amyloid beta] clearance mechanisms, resulting in the very rapid reversal of a broad range of [amyloid beta]-induced deficits”.
Speculating on their findings, Landreth and colleagues suggest that bexarotene reprogrammed the brain’s immune cells (the phagocytes, white blood cells that ingest unwanted material) to eat away the amyloid deposits. They believe their observations show that the drug stimulates removal of both soluble and deposited amyloid beta.
Human beings have three forms of gene that code for the ApoE protein: ApoE2, ApoE3, and ApoE4. People with the ApoE4 variant have a much greater risk for developing Alzheimer’s disease.
In a statement, Landreth described the study, which started as a “far-fetched idea”, as “particularly exciting and rewarding” because they have uncovered new information and the potential promise of a new treatment for Alzheimer’s disease. But he added a word of caution:
“We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment.”
In the meantime, he and his colleagues hope that, since bexarotene has a good safety and side-effect profile, these will help speed the transition to clinical trials.
Funds from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, and the National Institutes of Health helped pay for the study.
Written by Catharine Paddock PhD