by Tamara Bhandari•March 21, 2018
Alzheimer’s disease is characterized by clumps of two proteins – amyloid beta and tau – in the brain, but the link between the two has never been entirely clear. Now, researchers at Washington University School of Medicine in St. Louis have shown that people with more amyloid in the brain produce more tau, which could lead to new treatments for the disease based on targeting the production of tau.
It’s a paradox of Alzheimer’s 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 – known as tau – that show up years after the plaques first form. The link between amyloid and tau has never been entirely clear. But now, researchers at Washington University School of Medicine in St. Louis have shown that people with more amyloid in their brains also produce more tau.
The findings, available March 21 in the journal Neuron, 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,” said senior author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology.
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, Bateman and colleagues decided to measure how tau was produced and cleared from human brain cells.
Along with co-senior author Celeste Karch, PhD, an assistant professor of psychiatry, and co-first authors Chihiro Sato, PhD, an instructor in neurology, and Nicolas Barthélemy, PhD, a postdoctoral researcher, the researchers applied a technique known as Stable Isotope Labeling Kinetics (SILK). The technique tracks how fast proteins are synthesized, released and cleared, and can measure production and clearance in models of neurons in the lab and also directly in people in the human central nervous system.
Using SILK, 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 said.
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 said. “What we didn’t know was why. This explains the why: The presence of amyloid increases the production of tau.”
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 said.
“These findings point to an important new therapeutic avenue,” Karch said. “Blocking tau production could be considered as a target for treatment for the disease.”
Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TLS, Miller TM, Karch CM and Bateman RJ. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. March 21, 2018.
This work was supported by the National Institutes of Health (NIH), grant number R01NS095773, R01NS078398, K01 AG046374, K01 AG053474, P30DK056341, P01AG003991, UL1TR000448, P30NS098577, P50AG005681, and P01AG026276; Brightfocus Foundation, grant number A2014384S; the National Institute of Neurological Disorders and Stroke, grant numbers P01NS080675 and P30NS098577; Tau SILK Consortium (AbbVie, Biogen, and Eli Lily); Metlife Foundation; ALS Association; DIAN-TU; Hope Center for Neurological Disorders; The Foundation for Barnes-Jewish Hospital; Kanae Foundation for the Promotion of Science; McDonnell Science Grant for Neuroscience; the Tau Consortium; the Knight Alzheimer’s Disease Research Center; Coins for Alzheimer’s Research Trust; Alzheimer’s Association; and resources provided by Washington University Biomedical Mass Spectrometry Research Facility (NIH P41GM103422), Diabetes Research Center (NIH P30DK020579), and the Nutrition Obesity Research Center (NIH P30DK056341).
Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
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Tamara Bhandari, Senior Medical Sciences Writer
Tamara Bhandari covers pathology, immunology, medical microbiology, cell biology, neurology, and radiology. She holds a bachelor’s degree in molecular biophysics and biochemistry and in sociology from Yale University, a master’s in public health/infectious diseases from the University of California, Berkeley, and a PhD in infectious disease immunology from the University of California, San Diego.
In honor of ALzheimers and Brain Awareness Month, this has been reproduced with permission.