Alzheimer’s disease destroys brain cells, in part, by promoting the formation of insoluble clumps that contain a protein called tau. Not only are these “tau aggregates” toxic for the cells that harbor them, but they also invade and destroy neighboring brain cells, or neurons, which speed the cognitive decline associated with Alzheimer’s. For those reasons, Alzheimer’s researchers have been intensely interested in therapies aimed at either preventing tau aggregation or blocking its spread. Now, researchers in the UCLA Department of Neurology and at the UCLA School of Nursing have reported a promising drug strategy that blocks tau transmission.
A model of cambinol (small yellow structure near top center) binding to nSMase2 enzyme. Image: Kanagasabai Vadivel/UCLA Drug Discovery Lab
Using cultured cells, mouse models and protein structural analysis, researchers found that a small molecule called cambinol blocks the transfer of tau aggregates from cell to cell. The study could help lay the groundwork for therapies to treat Alzheimer’s or other dementias associated with the accumulation of tau. “More than 200 molecules have been tested as disease-modifying Alzheimer’s therapy in clinical trials, and none has yet attained the Holy Grail,” says Varghese John, PhD, associate professor of neurology. “Our paper describes a novel approach to slow Alzheimer’s progression by showing it is possible to inhibit propagation of pathologic forms of tau.”
In healthy people, tau proteins are benign building blocks of a neuron’s framework, or cytoskeleton. But in Alzheimer’s disease, tau proteins fall away from the cytoskeleton, become abnormally modified and then form insoluble “neurofibrillary tangles” that destroy cells. To make matters worse, dying cells encase tau aggregates in lipid vesicles called exosomes, which then bud off and “seed” neighboring tissues, keeping the destructive cycle going.
Researchers conducted several experiments that suggest that cambinol can subvert the “transfer” step by blocking an enzyme called nSMase2, which is essential for catalyzing production of the exosome carriers. In one, the scientists used “donor cells” that harbored tau aggregates derived from postmortem human Alzheimer’s specimens and mixed them with tau-free recipient cells.
Without cambinol, the aggregates spread from donors to recipients, mirroring what happens in the brains of people with Alzheimer’s. But when treated with cambinol, recipient cells remained tau-free when grown side by side with tau-positive donors, presumably because the drug disabled nSMase2 activity, blocking release of the tau-carrying exosomes.
The researchers also observed decreased nSMase2 catalytic activity in the brains of mice that were given cambinol orally. Dr. John says the seemingly routine experiment was an essential first step “because most drugs don’t penetrate the blood-brain barrier,” referring to the membranes that surround the central nervous system and keep drugs out of it. “Now we know we can treat animals with cambinol to determine its effect on Alzheimer’s pathology and progression.”
The research is the first to report on a model of how cambinol switches off nSMase2 catalytic activity at the atomic level, and it provides critical knowledge for medicinal chemists such as Dr. John to begin designing new drugs based on cambinol that are more potent and efficacious than the molecule itself.
“Suppression of Tau Propagation Using an Inhibitor that Targets the DK-switch of nSMase2,” Biochemical and Biophysical Research Communications, May 23, 2018
