Alzheimer’s Findings Suggest Future Restorative Treatment Interventions

Man poses for photo

Photo of Brendan Kelley, MD, by UC Academic Health Center Communications Services.

By Brendan Kelley, MD Director, Memory Disorders Center

Widespread media coverage of findings reported in Science  (published online 2/9/2012) by researchers at Case Western Reserve  University has renewed attention and interest in the development of  compounds that address the pathological changes that cause Alzheimer’s  disease.

The two pathological hallmarks of Alzheimer’s  disease involve abnormal processing of the proteins amyloid and tau. In  people who have Alzheimer’s disease, the body’s normal processing of the  protein amyloid is not functioning correctly, leading to accumulation  of the amyloid protein in the brain. This appears to be related to  impaired clearance (removal), although some research has also identified  overproduction of the more reactive (“sticky”) subtypes of the amyloid  protein as playing a role as well.

The  Case Western researchers reasoned that a molecule that might promote  clearance of amyloid may have a beneficial effect in the disease  pathogenesis. They used a mouse model of Alzheimer’s disease that has  been genetically modified to produce amyloid pathology in the brain  that resembles the changes seen in humans.

They administered a compound,  bexarotene, that interacts with a retinoid-X receptor  (RXR), with the hypothesis that this would increase clearance of amyloid  in these mice. Their study was positive, demonstrating changes in the  levels of both free and aggregated amyloid in the mouse brains. This  finding was seen both in young mice and older mice, suggesting the  effect may translate to more chronically deposited amyloid (although it  should be noted that “older mice” are 11 months old).

Fascinatingly, the mice also exhibited behavioral  changes when treated with the drug. There were improvements in a memory  task, a fear-conditioning task following more chronic treatment. As featured in an article in the Wall Street Journal,  treated mice appear to have exhibited behavioral changes related to  nest building as well. Thus, both instrumental and complex behaviors  appear to have been improved in those mice treated with bexarotene.

These are exciting findings. The behavioral changes  provide a persuasive suggestion that cognition in Alzheimer’s disease  may be amenable to future restorative treatment interventions. The study  illustrates a new potential therapeutic target (namely the RXRs), which  will certainly spur further research and increase our understanding of  the pathological causes of Alzheimer’s disease. The compound,  bexarotene, will certainly merit further investigation. As we have seen  previously, test results in mice do not always correlate to a similar  effect in humans, and further study of dosing, safety and side effects  will be required before a clinical trial using this compound in humans  would be appropriate. Nonetheless, this important research finding will  advance our understanding of Alzheimer’s disease, drawing us one step  closer to identifying effective treatment strategies and ultimately a  cure.

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