Summary: Researchers identify how taupT217, a toxic form of the Tau protein, spreads in the brain as Alzheimer’s disease progresses.
Source: University of Virginia
University of Virginia neuroscientists have revealed how a toxic form of tau protein, known to form tangles in the brains of people with Alzheimer’s disease and several other neurodegenerative disorders, spreads through the brain as the disease progresses.
The tau protein helps cause the cognitive decline associated with these diseases. Research shows what causes it to build up and how it harms nerve cells called neurons. Scientists may be able to use these findings to develop new treatments for Alzheimer’s disease that prevent or delay the onset of symptoms, or slow disease progression once symptoms develop.
UVA’s new research also advances efforts to develop blood tests to detect Alzheimer’s disease in its earliest stages, when it is, in principle, most likely to be treated. The researchers found that the antibodies used in blood tests to measure this toxic, chemically altered form of tau, called “taupT217”, can easily be tricked into detecting other proteins, compromising the accuracy of the test. Fortunately, they also showed how this problem can be avoided.
The new research from Dr. George Bloom and colleagues at UVA is the most comprehensive review to date of where and how taupT217 accumulates in the brain. The results provide essential information about the development of Alzheimer’s disease and possibly other neurological conditions called “non-Alzheimer’s tauopathies.”
These include Parkinson’s disease and chronic traumatic encephalopathy.
“Recent years have seen exciting advances in the early detection of Alzheimer’s disease by measuring the amount of taupT217 in blood or cerebrospinal fluid, but so far almost nothing has been learned about what causes this type of tau to form in the brain or how it affects neuronal health,” said Bloom, from UVA’s departments of biology, cell biology and neuroscience, as well as the ‘UVA Brain Institute, the Virginia Alzheimer’s Disease Center and the UVA Program in Basic Neuroscience.
“Knowing what causes taupT217 to build up in the brain and how it harms neurons offers new avenues for therapeutic intervention,” he said.
Understanding Alzheimer’s
Tau plays an important role in the healthy brain, where, among other things, it helps build and maintain “microtubules” that serve as highways for transporting important materials into neurons that form brain circuits. But in people with Alzheimer’s disease, tau is chemically altered and distorted in ways that prevent it from working normally and make it toxic. This ultimately leads to two phenomena that explain cognitive decline in Alzheimer’s disease: the destruction of neural circuits and the death of neurons.
Why this happens has only been partially understood, but new UVA research offers more answers. For example, the researchers found that they could trigger the accumulation of taupT217 in cultured neurons by exposing them to clumps, or oligomers, of tau. These are known to accumulate in the brain in Alzheimer’s disease and have long been suspected of being a harmful contributor to the disease.
They also found that the chemical modification that converts normal tau to taupT217 dramatically decreases the ability of tau to adhere to microtubules, which may facilitate the formation of toxic oligomers by tau.
“In terms of immediate clinical value, we hope that our findings on the challenge of antibody specificity to measure taupT217 in blood will quickly resonate with companies striving to develop commercially available tests to identify patients. with Alzheimer’s years before symptoms became evident,” Bloom said. .
“Because massive and irreversible brain damage has already occurred when symptoms appear, accurate early diagnosis will be crucial for the development of drugs that effectively combat Alzheimer’s disease.”
This is just one example of the practical knowledge generated by UVA research that will benefit efforts to better diagnose and treat Alzheimer’s disease.
“Alzheimer’s disease reflects a multidimensional breakdown of normal brain cells, so there’s nothing simple about it,” Bloom said. “Focusing research on the early processes that convert normal brains into Alzheimer’s brains, however, offers the best hope of eventually defeating this terrible disease.”
The researchers published their findings in the journal Alzheimer’s and dementia. The first author of the article is Binita Rajbanshi, a recent graduate with a doctorate in pharmacology. student. Other team members were Anuj Guruacharya, James Mandell and Bloom. The scientists said they had no financial interest in the work.
See also
About this Alzheimer’s disease research news
Author: Josh Barney
Source: University of Virginia
Contact: Josh Barney – University of Virginia
Picture: Image is in public domain
Original research: Free access.
“Localization, induction and cellular effects of threonine 2171 phosphorylated tau” by Binita Rajbanshi et al. Alzheimer’s and dementia
Summary
Localization, induction and cellular effects of threonine phosphorylated tau 217 1
Introduction
Tau phosphorylation at T217 is a promising biomarker of Alzheimer’s disease (AD), but its functional consequences were unknown.
Methods
Human brain and mouse neurons in culture were analyzed by immunoblotting and immunofluorescence for total tau, taupT217yespT181yespT231and yearspS396/pS404. Direct Stochastic Optical Reconstruction Microscopy (dSTORM) Super-resolution microscopy was used to localize taupT217 in cultured neurons. Enhanced green fluorescent protein (EGFP)-tau was expressed in fibroblasts as wild-type pseudo-phosphorylated tau and T217E, and fluorescence recovery after photobleaching (FRAP) reported tau turnover rates on microtubules.
Results
In the brain, taupT217 appears in neurons at Braak stages I and II, becomes more frequent later, and partially co-localizes with other phospho-tau epitopes. In cultured neurons, taupT217 is increased by extracellular tau oligomers (xcTauOs) and is associated with the development of postsynaptic sites. FRAP recovery was fastest for EGFP-tauT217E.
Conclusion
YespT217 increases in the brain as AD progresses and is induced by xcTauOs. Post-synaptic taupT217 suggests a role of T217 phosphorylation in synapse damage. Phosphorylation of T217 reduces tau affinity for microtubules.