Pharmacological chaperone therapy shown to prevent Alzheimer’s in mice

Scientists have shown that pharmacological chaperones could fill a critical role in Alzheimer’s disease therapy and in a new study have described a novel pharmacological chaperone capable of preventing Alzheimer’s disease in animals prone to developing the condition.

Proteins that begin to lose their shape tend to clump together and when this happens, old or dysfunctional proteins become trapped within cellular compartments and eventually cause major problems. Fortunately, cells are equipped with molecular machinery that prevents them from accumulating and causing harm. In recent years, scientists have developed small drug molecules, known as pharmacological chaperones, that can help in this process.

This study is the first to show that a pharmacological chaperone drug can effectively disrupt the abnormal processes that damage neurons in the brain, fuel memory loss and ultimately give rise to Alzheimer’s disease.

“Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation,” explained Dr Domenico Praticò, Director of the Alzheimer’s Center at Temple in the Lewis Katz School of Medicine, US and senior investigator on the new study.

The researchers in this study investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer’s disease as they age. They found that, compared to untreated mice destined for Alzheimer’s disease, the treated animals had much better memory and behaved just like normal mice. When the researchers examined neurons from treated mice, they observed significant decreases in tau tangles, as well as decreases in amyloid-β plaques – another type of protein aggregate that contributes to Alzheimer’s disease.

The researchers further noticed that VPS35 levels were restored and the junctions where neurons come together to exchange information were fully functional following the pharmacological chaperone therapy.

“Relative to other therapies under development for Alzheimer’s disease, pharmacological chaperones are inexpensive and some of these drugs have already been approved for the treatment of other diseases,” Praticò said. “Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer’s treatments.”

Before moving to trials in human patients, however, Praticò plans to next investigate the effects of pharmacological chaperone therapy in older mice: “Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer’s disease.”

The study was published in Molecular Neurodegeneration.