Alzheimer’s disease has two hallmarks: protein clumps, called plaques, that cluster outside of neurons, and twisted protein fibers, called tangles, that build up inside neurons. In the vast majority of Alzheimer’s cases, scientists don’t know what triggers build-up of these proteins, and they have been arguing heatedly for years about whether plaques or tangles are the true culprit behind the devastating cognitive decline caused by the disease.
Now scientists at Harvard have identified an enzyme that can block build-up of both plaques and tangles in cellular models – a finding that could help link these two perplexing neurological problems and provide a new avenue for drug development.
[For images of the enzyme in action, click here.]
“[The enzyme] could be a universal regulator of AD pathology…With one molecule you might be able to target and correct two major problems of the disease,” says Rudy Tanzi, a neurogeneticist at Massachusetts General Hospital and Harvard Medical School in Boston (who was not involved in the research). “Whether it will do that, time will tell…but I think the findings will trigger a lot more work on [this enzyme,] so at the end of day we’ll know if it represents a good drug target.”
Both plaques and tangles are caused by the abnormal build-up of proteins. Tangles are made up of a protein called tau, while plaques are made up of fragments of a protein called amyloid precursor protein (APP). In Alzheimer’s patients, both those proteins undergo chemical changes that make them more likely to clump together.
In previous research, Kun Ping Lu, a biologist at Beth Israel Deaconess Medical Center and Harvard Medical School, found that an enzyme called Pin1 reverts the tau protein back to its healthy conformation, thereby preventing the formation of tangles.
In the current paper, published today in the journal Nature, Lu and colleagues showed that Pin1 could also restore the APP protein to its normal shape, preventing the build-up of the toxic fragment that accumulates in plaques. “Pin1 is like the oil in a car engine. You need oil to keep it running smoothly; without it, things begin to break down. If you don’t have Pin1, proteins become misshapen and aggregate into tangles or plaques,” says Lu.
The findings could aid the ongoing quest in Alzheimer’s biology to find a single chemical, biological, or genetic change that might lead to both plaques and tangles, says Sam Gandy, chair of the Alzheimer’s Association Medical and Scientific Advisory Council and director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia. “This is a good candidate for looking for that final common pathway. Pin1 provides a single molecule that could interact and potentially cause both features of pathology,” says Gandy.
More work is needed, Gandy says, before scientists can determine the true role of Pin1 in the human brain and in Alzheimer’s. “The data in this paper are pretty dramatic…I would like to see it verified in some mouse models of plaque pathology,” he says.