A brain protein called tau is known to play a key role in the development of Alzheimer’s disease.
Our brain cells have a “transport system” made of straight, parallel “roads,” along which food molecules, nutrients, and discarded parts of cells can travel.
In a healthy brain, the protein tau helps these tracks to stay straight. However, in Alzheimer’s, the protein builds up to abnormal levels, forming harmful structures called tangles.
Initially, these tangles form in brain areas key for memory formation, but as the disease progresses, the tangles continue to spread throughout the rest of the brain.
However, researchers at the University of California, Los Angeles (UCLA) might now have found a way to stop the spread of these damaging tangles.
Their new study — published in the journal Biochemical and Biophysical Research Communications — shows how a small molecule called cambinol stops tau tangles from migrating from cell to cell.
Senior study author Varghese John, an associate professor of neurology at UCLA, comments on the significance of the findings, saying, “Over 200 molecules have been tested as disease-modifying Alzheimer’s therapy in clinical trials, and none has yet attained the holy grail.”
“Our paper describes a novel approach to slow Alzheimer’s progression by showing it is possible to inhibit propagation of pathologic forms of tau.”
Cambinol blocks tau transfer
In a healthy brain, the tau protein ensures that the tracks stay straight by binding to microtubules, which form the skeleton of the cells.
But in Alzheimer’s, tau detaches and “falls off” from the skeleton, creating so-called neurofibrillary tangles instead, which causes the brain cells to die.
The situation aggravates when these brain cells continue to enclose tau clumps, or aggregates, into small pockets that then migrate and “take root” in the surrounding healthy tissue.
These small lipid pockets, or vesicles, are called exosomes. They ensure the continued spread of tau tangles. But what if there was a way to block the very formation of these “carrier bags” for the toxic tau protein?
Analyzing the behavior of the tau protein in vitro (in cell cultures) and in vivo (using mouse models), the researchers found that cambinol has the ability to do just that: it hijacks the transfer of tau by blocking an enzyme called nSMase2, which is key for producing the tau-carrying exosomes.
In one experiment, the scientists used tau-carrying cells obtained postmortem from the brains of humans who had had Alzheimer’s. They mixed these cells with tau-free cells.
The tau aggregates continued to spread in the cells that had not been treated with cambinol. But in those that did receive the treatment, the new and healthy cells were not “contaminated” with tau.
Toward new Alzheimer’s drugs
The researchers think that these hopeful results are due to cambinol inhibiting the activity of the nSMase2 enzyme, and that this mechanism could provide a great basis for future drug development.
In fact, in a second in vivo experiment, the researchers saw that the activity of the enzyme was reduced in the brains of mice treated with cambinol. This was particularly promising.
“Getting molecules into the brain is a big hurdle, because most drugs don’t penetrate the blood-brain barrier,” explains John. “Now we know we can treat animals with cambinol to determine its effect on Alzheimer’s pathology and progression.”
To the authors’ knowledge, this was the first study to have shown that cambinol suppresses the activity of the nSMase2 enzyme. The findings bring us closer to new treatments for Alzheimer’s disease, as well as for other conditions characterized by tau aggregates.
“Understanding pathways is the first step to new drug targets,” says study co-author Karen Gylys, a UCLA professor of nursing.
“With cambinol in hand, we have a useful tool for understanding cellular pathways that enable the spread of tau pathology.”
The researchers are now working to design drugs that make cambinol more potent, and they are hopeful that their work will prove successful in animals.
If that is the case, the next step will be testing the new drugs in human clinical trials.
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