Researchers have discovered a link between two proteins related to Alzheimer’s disease, tau and amyloid beta, finding that people with more amyloid in their brains also produce more tau.
It’s a paradox of the disease: Plaques of the sticky protein amyloid beta are the most characteristic sign in the brain of the deadly neurodegenerative disease. However, many older people have such plaques in their brains but do not have dementia.
The memory loss and confusion of Alzheimer’s instead is associated with tangles of a different brain protein—tau—that show up years after the plaques first form.
“We think this discovery is going to lead to more specific therapies targeting the disease process.”
The link between the two has never been entirely clear—until now. The findings could lead to new treatments for Alzheimer’s, based on targeting the production of tau.
“We think this discovery is going to lead to more specific therapies targeting the disease process,” says Randall Bateman, distinguished professor of neurology at Washington University in St. Louis and senior author of the new paper, which appears in Neuron.
Years ago, researchers noted that people with Alzheimer’s disease have high levels of tau in the cerebrospinal fluid, which surrounds their brain and spinal cord. Tau—in the tangled form or not—is normally kept inside cells, so the presence of the protein in extracellular fluid was surprising.
As Alzheimer’s disease causes widespread death of brain cells, researchers presumed the excess tau on the outside of cells was a byproduct of dying neurons releasing their proteins as they broke apart and perished. But it was also possible that neurons make and release more tau during the disease.
In order to find the source of the surplus tau, researchers decided to measure how tau was produced and cleared from human brain cells.
The researchers applied a technique known as Stable Isotope Labeling Kinetics (SILK) that tracks how fast proteins are synthesized, released, and cleared, and can measure production and clearance models of neurons in the lab and also directly in people in the human central nervous system.
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The researchers found that tau proteins consistently appeared after a three-day delay in human neurons in a laboratory dish. The timing suggests that tau release is an active process, unrelated to dying neurons.
Further, by studying 24 people, some of whom exhibited amyloid plaques and mild Alzheimer’s symptoms, they found a direct correlation between the amount of amyloid in a person’s brain and the amount of tau produced in the brain.
“Whether a person has symptoms of Alzheimer’s disease or not, if there are amyloid plaques, there is increased production of this soluble tau,” Bateman says.
The findings are a step toward understanding how the two key proteins in Alzheimer’s disease—amyloid and tau—interact with each other.
“We knew that people who had plaques typically had elevated levels of soluble tau,” Bateman says. “What we didn’t know was why. This explains the why: The presence of amyloid increases the production of tau.”
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Tau is strongly linked to brain damage, so overproduction of the protein could be a critical step in the development of Alzheimer’s, and reducing tau’s production may help treat the disease, the researchers say.
“These findings point to an important new therapeutic avenue,” Karch says. “Blocking tau production could be considered as a target for treatment for the disease.”
