In Alzheimer’s, scientists have hypothesized that dying brain cells break apart and release proteins, including tau, which then form the tangles that are a hallmark of the disease. New research from Washington University in St. Louis shows, however, that tau secretion is actually an active process, not a byproduct of cell death—findings that could refine tau-targeting treatments for Alzheimer’s.
The research could also explain why experimental tau-focused treatments haven’t fared better in treating patients with the disease.
A variety of approaches are in the works to address the dearth of new Alzheimer’s treatments. Many of them focus on another key protein, amyloid, and its contribution to the formation of brain plaques. A Johns Hopkins team landed on a chain of signaling events by which amyloid buildup causes the clumping of tau, while Yale scientists found that a problem in lysosome transport may contribute to the accumulation of amyloid plaques. Other methods include targeting genetic variants in neurological cells to boost the immune system’s ability to fight Alzheimer’s.
The Washington University team, led by Randall Bateman, a professor of neurology, focused on tau using mass spectrometry and a technique called Stable Isotope Labeling Kinetics (SILK) to measure the production and clearance of tau proteins in neurons and cerebrospinal fluid.
Neurons made from induced pluripotent stem cells produced new tau after a three-day delay, suggesting that tau synthesis is an actively regulated process, according to the study, which appeared in the journal Neuron. The team also looked at tau in cerebrospinal fluid from healthy people and from those known to have Alzheimer’s, finding a direct correlation between the amount of amyloid in a person’s brain and the amount of tau produced in the brain.
The research also shed light on different forms of tau and their turnover rate: “[The] forms of tau that are turned over more quickly are also those that are prone to misfold and aggregate in the context of Alzheimer's disease and other tauopathies,” said co-author Celeste Karch, an assistant professor of psychiatry at WUSTL.
“We've known for a long time that tau [in cerebrospinal fluid] is increased in Alzheimer's disease, but until this study, we didn't know if tau production was increased or if clearance was decreased," said Chihiro Sato, a member of the Bateman lab and one of the paper's co-first authors. "Our results showing that tau production is increased suggest that we might want to target tau production therapeutically."