Abstract
Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau’s ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.
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Acknowledgments
We thank Jian Yang, Norbert Lee, and Stephanie Gaus for technical assistance, and our patients and their families for their invaluable contributions to neurodegenerative disease research. Funding was provided by National Institute of Health (NIH) P50 AG023501 to B.L.M. and W.W.S., Tau Consortium (to L.G. and W.W.S.), NIH R01AG030207 (to L.G.), NIH R01AG040311 to L.T.G., the John Douglas French Alzheimer’s Disease Foundation (to L.T.G. and W.W.S.), the Consortium for Frontotemporal Dementia Research (to W.W.S).
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L. Gan and W. W. Seeley contributed equally.
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401_2013_1080_MOESM1_ESM.tif
Online resource 1 Antigen competition assay. a inferior temporal cortex of an AD case (case # 3) after immunohistochemistry with MAb 359. Note the plaques and tangles in dark brown. b higher magnification of (a). The plaques and tangles can be visualized in detail. c a parallel slide to (a) after immunohistochemistry with MAb 359 pre-incubated with the antigen used for its generation. All the other reaction steps were the same as in (a). Note that the reaction was negative, supporting MAb 359 specificity against tau acetylated at position 274. d higher magnification of (b). Scale bars represent 500 μm in a and c, and 100 μm in b and d. (TIFF 4699 kb)
401_2013_1080_MOESM2_ESM.tif
Online resource 2 Inferior temporal cortex of Pick’s disease (case 18) after immunofluorescence with CP-13 (a) and MAb 359 (b) antibodies. Pick bodies are both phosphorylated (a) and acetylated (b). Most of the inclusions have both changes and the processes are mainly phosphorylated only (c). Scale bar represents 50 μm (TIFF 4050 kb)
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Online resource 3 Across all tauopathies, neuronal processes were rarely ac-tau positive. This figure shows parallel sections of the hippocampal dentate gyrus granule cell (top of the figure) and molecular layers (bottom of the figure) in Alzheimer’s disease (case 3) immunostained with (a) CP-13 and (b) MAb 359. Note the strong phospho-tau positivity and absent ac-tau positivity in the external portion of the molecular layer. The dentate gyrus molecular layer contains abundant axons and dendrites. This figure demonstrates the remarkable discrepancy between phosphor-tau and ac-tau changes in neuronal processes. The arrow in b shows an acetylated tau-positive neurofibrillary tangle as an internal positive control. (TIFF 2268 kb)
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Grinberg, L.T., Wang, X., Wang, C. et al. Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125, 581–593 (2013). https://doi.org/10.1007/s00401-013-1080-2
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DOI: https://doi.org/10.1007/s00401-013-1080-2