Along with amyloid-beta, tau and phosphorylated tau are among the most promising protein biomarkers for Alzheimer's disease. Now, research suggests that acetylated tau might also be a biomarker for the disorder.
In a study published last month in the online edition of Nature Communications, University of Pennsylvania scientists demonstrated that acetylated tau protein is found in the brain tissue of patients with Alzheimer's disease and frontotemporal lobe degeneration but not in the tissue of healthy subjects. The study also showed that, similar to phosphorylation, tau acetylation promotes pathological aggregation of the protein by inhibiting its interaction with microtubules.
"Acetylation appears to have the same effect as phosphorylation in that both modifications seem to reduce the binding of tau to microtubules," Virginia Lee, director of Penn's Center for Neurodegenerative Disease Research and an author on the paper, told ProteoMonitor.
Preliminary data from the work also suggests a link between acetylation and phosphorylation, Lee said, noting that while further study is need to establish the exact relationship, increases in acetylation seem to be accompanied by increased phosphorylation.
The investigation of tau as a protein biomarker for Alzheimer's has been led in large part by Lee's fellow Penn researchers Les Shaw and John Trojanowski – the latter of which was a co-author on the Nature Communications paper.
Initial studies by these two researchers determined that a pathological cerebrospinal fluid biomarker signature of Alzheimer's could be defined by the combination of amyloid-beta1-42 and total tau protein levels, and using the signature, they were able to predict roughly 90 percent of the time which patients would progress from mild cognitive impairment to Alzheimer's (PM 06/11/2010).
Work to clinically validate these biomarkers is still ongoing, however, and there has been some difficulty in reproducing CSF protein biomarker measurements across laboratories.
Because Alzheimer's likely begins long before the appearance of cognitive symptoms in patients, the identification of biomarkers for early detection and progression is key to developing treatments for the disease. To assess acetylated tau's potential as a marker, Lee's team now plans to look for it in the CSF of Alzheimer's patients to see if it can be picked up in that media.
"We don't know whether or not acetylation is as extensive as phosphorylation," she said, noting that this could make it more difficult to detect. "We need to do the experiment. A priori, I don't think we can really predict what's going to happen."
If acetylated tau can be detected in CSF, it could serve not only as an additional Alzheimer's biomarker, but also as a protein marker for distinguishing between different types of frontotemporal lobar degeneration. This, Lee said, could actually be more important than its potential as a tool for Alzheimer's diagnoses, because while several good biomarker candidates for that disease already exist, there are currently no markers for distinguishing between types of FTLD.
FTLD encompasses a range of disorders associated with atrophy in the frontal and temporal lobes of the brain. It includes both diseases associated with pathological tau aggregation and disorders associated with the activity of the protein TDP-43. The difficulty, Lee noted, is in telling these classes of disease apart.
Unlike in Alzheimer's disease, patients with tau-related FTLD don't have elevated levels of tau and phosphorylated tau in their CSF. And while TDP-43 is being studied as a potential biomarker, that work, Lee said, is "happening relatively slowly, and we don't know yet if it will actually be useful."
The discovery of acetylated tau in the brain tissue of Alzheimer's and FTLD patients raises the possibility, she said, that "acetylated tau in FTLD tauopathies is increased compared to FTLD [associated with] TDP-43 because of the fact that the brains of [tau association] FTLD patients have a lot of acetylated tau modification."
Such a biomarker would be important because "if you have a treatment for the tau pathology, you don't want to treat the patients with the TDP-43 pathology with that drug," Lee said. "These two proteins have totally different functions. One is a DNA-binding protein, and one is associated with stabilizing microtubules. So it's critical that we come up with something that distinguishes between [the two]."
Lee noted that her lab will look first at acetylated tau's usefulness as an Alzheimer's biomarker, however, due to the Center for Neurodegenerative Disease Research's large collection of samples from Alzheimer's patients.
"Alzheimer's is the first place we're going to look. We're in a unique position in the sense that we have a large bank of biofluids," she said. "We have a lot of samples and we have good clinical histories of the patients and longitudinal follow-up of the patients, and in some cases when these patients expired they donated their brains, so we even have the brains of some patients."
Although Lee's colleagues Shaw and Trojanowski are the co-directors of the Alzheimer's Disease Neuroimaging Initiative's Biomarker Core, her work is unaffiliated with that initiative. If her team is able to develop a promising biomarker assay for acetylated tau, it could be passed on to ADNI researchers for further work and optimization, she said.
"What I do is a lot of early development of assays that, if they can be developed as a lab test, I would hand over to Les and John," she said. "The idea is I do this separately. It's not funded by ADNI. But if anything shows promise in a research setting then it can be used in a more standardized way to test the ADNI samples and be incorporated as one of the biomarkers that they'll look at in their assays."
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