A new approach to treating Alzheimer’s disease

A stronger cellular disposal system may slow the progress of Alzheimer’s

Cellular processes are not perfect. They, like us, make mistakes. Sometimes, the by-products of those mistakes are harmless. Other times, they can lead to disease or even death. 

With Alzheimer’s disease, the mistake occurs when a protein called amyloid precursor protein (APP) in a neuron’s membrane is cut in the wrong place, leading to a buildup of abnormal fragments called amyloid-beta. These fragments clump together to form a plaque around neurons, eventually interfering with brain function. 

But the cell has systems to deal with mistakes. A protein complex called retromer acts like a cellular garbage truck, collecting faulty gene products and trafficking them to be destroyed or recycled. 

For years, Alzheimer’s research has focused on preventing the formation of amyloid-beta with little success. But instead of trying to stop mistakes, what if researchers improved the system for dealing with them? 

A team of researchers from Brandeis University, Columbia University Medical Center (CUMC) and Weill Cornell Medical College did just that. They have devised a novel approach to the treatment of Alzheimer’s disease that significantly increases retromer levels while decreasing amyloid-beta levels in neurons, without harming the cell. 

The study was published April 20 in the online edition of the journal Nature Chemical Biology.

At Brandeis, Dagmar Ringe, the Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and Gregory Petsko, professor emeritus of biochemistry and chemistry, led the research team, which included former student Vincent Mecozzi, PhD ’12, and Mehraj Awal ’14.

Previous research showed that brains affected by Alzheimer’s had lower levels of retromer and by increasing retromer in neurons, amyloid-beta levels decreased. However, this is the first time researchers have found a way to pharmacologically strengthen the retromer complex.  

The scientists identified compounds called pharmacological chaperones that bind to retromer’s weakest points, making the complex stronger, more resilient and better able to move amyloid-beta.  

When the chaperone, named R55, was added to neurons in cell culture, it bound to and stabilized retromer — like reinforcing a garbage truck with stronger parts. Researchers saw an almost immediate increase in retromer levels and a decrease in amyloid-beta levels.

The researchers are currently testing the clinical effects of R55 in mice.

Ringe cautioned that this research is not a cure for Alzheimer’s but a potential treatment. 

“This research cannot stop the progress of Alzheimer’s once it is diagnosed,” she says. “But what it can do is ameliorate it and slow down that progress, which is a very good start.”

The research was funded in part by the National Institutes of Health (AG025161 and AG08702), the Alzheimer's Association, Medkoo Biosciences and the Fidelity Biosciences Research Initiative.

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