Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation
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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.
KeywordsTau Pathology Autopsy Acetylation Immunohistochemistry Human
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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