‘Pharmacological Chaperones’ May Help Treat Alzheimer’s By Clearing Harmful Proteins From Brain

Decades ago, a chaperone was a person who accompanied an unmarried girl in public. Now, however, we’re learning that a chaperone — in this case a pharmacological chaperone, or a small drug molecule — might help clear the brain of the beta amyloid proteins believed to contribute to the development of Alzheimer’s disease.

In a study published in the journal Molecular Neurodegeneration, researchers at the Lewis Katz School of Medicine at Temple University in Philadelphia describe what they call a “novel pharmacological chaperone capable of preventing Alzheimer’s disease in animals prone to developing the condition.”

The researchers said their 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.

In the body, cellular proteins are inherently unstable and can often become misshaped. In healthy brains, a molecule known as VPS35 acts as a sorter, separating out dysfunctional and old proteins and sending them off for destruction.

In previous work, the Temple researchers demonstrated that that VPS35 actively clears the brain of potentially harmful proteins such as beta amyloid and tau. But they found that in Alzheimer’s, VPS35 levels are reduced, which allows for the accumulation of the amyloid proteins and tau tangles that degrade neurological function.

“Our chaperone drug specifically restored levels of a sorting molecule known as VPS35,” Domenico Praticò, the senior investigator on the new study and the Director of the Alzheimer’s Center at Temple, said in a news release.

Praticò also said that compared to other potential therapies under development for Alzheimer’s, pharmacological chaperones are inexpensive and some have already been approved for the treatment of other diseases.

“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,” he said. “All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer’s treatments.”

In the new study, the researchers investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer’s disease as they age. Mice were treated from a young age, before they began to show signs of disease. As the animals grew older, they were tested for effects on memory and learning.

Compared to untreated mice destined for Alzheimer’s disease, the Temple researchers found that the treated animals had much better memory and behaved just like normal mice.

When the researchers examined neurons from treated mice, they said they found significant decreases in tau tangles, as well as decreases in beta amyloid plaques. The researchers further found that VPS35 levels were restored and the junctions where neurons come together to exchange information, known as synapses, were fully functional following the pharmacological chaperone therapy.

The researchers said that human trials are not imminent and that they would 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,” Praticò said.

In 2017, Being Patient spoke with Dr. Roxana Carare, a professor of clinical neuroanatomy and experimental neuropathology at the University of Southampton, about how the body clears protein plaques from the brain. Read that interview here.