Boosting Proteins Could Help Remove Tangles and Plaques Associated With Alzheimer's

Research conducted at Temple University is showing a potential new way to address the onset of Alzheimer’s disease through the use of pharmacological chaperones.

The study, undertaken at the Lewis Katz School of Medicine at Temple, shows that boosting levels of a protein within the body through a small molecule can help clear away levels of amyloid plaque associated with the severe form of dementia. The role of the pharmacological chaperone, small drug molecules, can help the body rid itself of the clumps of dysfunctional proteins. The study in mice, which was published in the journal Molecular Neurodegeneration, is the first to show that the use of a pharmacological protein can disrupt the process that damages the neurons in the brain. First reported in Eureka Alert, the study shows that the use of the chaperone was able to restore levels of VPS35, a sorting molecule that helps with the elimination of the old proteins that have clumped together and become too difficult for the body to remove on its own.

Domenico Praticò, the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine, told Eureka Alert that the chaperone drug the researchers were using restored the levels of VPS35 and allowed them to remove the endosomes, which he described as “compartments inside cells where proteins are sorted for degradation.” VPS35 plays an essential role in the process by removing those old and dysfunctional proteins and allowing the body to recycle them.

As Eureka Alert explains, Praticò and his colleagues have previously shown that VPS35 actively clears the brain of potentially harmful proteins such as amyloid beta and tau. In Alzheimer’s disease though, the levels of VPS35 are reduced, which then leads to the rise of tau tangles and the development of plaque inside and outside the neurons. But, by boosting levels of VPS35, the researches saw a response in mice. The mice were treated with VPS35 prior to their showing signs of the disease, and as they grew older, they had a better memory and behaved like the control mice. The researchers also noted that VPS35 levels were restored and the synapses in the brain “were fully functional following the pharmacological chaperone therapy.”

Praticò said that pharmacological chaperones are fairly inexpensive, particularly in comparison to some of the other medications in development for Alzheimer’s. What’s more, he said that some have already been approved for use in other diseases.

“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,” Praticò told Eureka Alert.

The next step in the research process is to test the pharmacological chaperone in older mice, which could lend an idea of whether or not the treatment could work in patients who have already been diagnosed with Alzheimer’s disease.