Authors: Majerova, Petra | Barath, Peter | Michalicova, Alena | Katina, Stanislav | Novak, Michal | Kovac, Andrej
Article Type: Research Article
Abstract: Alzheimer’s disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model …for tauopathy expressing human truncated tau protein (aa 151–391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography – matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation. Show more
Keywords: Cerebrospinal fluid, LC-MALDI MS, peptidomics, rat model, tauopathy
DOI: 10.3233/JAD-170110
Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 507-520, 2017
Authors: Banks, William A. | Kovac, Andrej | Majerova, Petra | Bullock, Kristin M. | Shi, Min | Zhang, Jing
Article Type: Research Article
Abstract: Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer’s disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151–391 (0N4R), and truncated tau 121–227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau …proteins also entered the blood after their injection into the brain, with Tau 121–227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease. Show more
Keywords: Alzheimer’s disease, blood-brain barrier, tau protein, tauopathy
DOI: 10.3233/JAD-160542
Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 411-419, 2017
Authors: Paholikova, Kristina | Salingova, Barbara | Opattova, Alena | Skrabana, Rostislav | Majerova, Petra | Zilka, Norbert | Kovacech, Branislav | Zilkova, Monika | Barath, Peter | Novak, Michal
Article Type: Research Article
Abstract: Tau protein is a member of microtubule-associated protein family. Under pathological conditions, tau undergoes multiple modifications that lead to the formation of insoluble deposits in neurons, resulting in neuronal dysfunction in several neurodegenerative disorders collectively called tauopathies, with Alzheimer's disease being the most frequent example. This typical cytosolic protein has been shown to translocate into the nucleus and participate in DNA protection upon stress conditions. In our study, we demonstrate that truncated Tau151-391/4R changes its usual behavior and gains constitutive access into the nucleus of both primary rat neurons and human neuroblastoma cells. Our results show that partial/dysregulated nuclear localization …of tau results from the removal of the N-terminal (1–150) residues of the protein. Data obtained by cell fractionation data were supported by confocal microscopy analysis of GFP-fused tau proteins. Furthermore, neither addition of the fusion protein, nor increased tau phosphorylation had any effect on the intracellular distribution of truncated tau. Our data further suggest that differential tau phospho-status between cytosolic and nuclear fractions is rather a consequence than a cause of truncated tau nuclear localization. Finally, truncated tau in the nucleus is engaged in interactions with subnuclear structure(s), since it exhibits reduced mobility. We conclude that N-terminal truncation of tau proteins leads to their nonphysiological subcellular distribution as a result of modified tau conformation. Show more
Keywords: Alzheimer's disease, cell compartmentation, cell nucleus, neurodegenerative diseases, tau proteins, truncation
DOI: 10.3233/JAD-140996
Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 915-926, 2015