Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies

Centre for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Centre, Institute on Ageing, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA.
Brain (Impact Factor: 9.2). 03/2012; 135(Pt 3):807-18. DOI: 10.1093/brain/aws013
Source: PubMed


The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.

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    • "KXGS motifs were found to be hypoacetylated and hyperphosphorylated in patients with AD, consistent with in vitro data showing that the acetylation of tau prevents its phosphorylation and inhibits tau aggregation (Irwin et al., 2013; Cook et al., 2014). In contrast, acetylation of tau at K280 was associated with phosphorylation at the AT8 epitope in tau aggregates of tau transgenic mice, and detected in post-mortem tissue of cases with AD or other tauopathies (Min et al., 2010; Cohen et al., 2011; Irwin et al., 2012). Recent evidence was provided that tau itself possesses acetyltransferase activity, and is capable of catalyzing self-acetylation (Cohen et al., 2013). "
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    • "SIRT1 levels correlate negatively with the amount of neurofibrillary tangles in AD brains (Julien et al., 2009), and this association suggests a possible pathogenic role of SIRT1 deficiency in tau accumulation. Indeed, tau was acetylated in the early and late stages of tauopathies (Min et al., 2010; Cohen et al., 2011; Irwin et al., 2012; Grinberg et al., 2013). Aberrant tau acetylation has a key role in tau accumulation and dysfunction (Min et al., 2010; Cohen et al., 2011; Irwin et al., 2012; Grinberg et al., 2013). "
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    • "Other potential post-translational modifications in the RD4 epitope include acetylation and methylation on K280 [14-16]. Using antibodies specific for tau acetylated at lysine 280, significant acetylated-tau pathology has been found with a distribution pattern similar to that of hyperphosphorylated tau [15]. However, in our protein chemical analyses (including LC/MS/MS) of AD tau, such modification has not been clearly detected. "
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    ABSTRACT: Intracytoplasmic inclusions composed of filamentous tau proteins are defining characteristics of neurodegenerative tauopathies, but it remains unclear why different tau isoforms accumulate in different diseases and how they induce abnormal filamentous structures and pathologies. Two tau isoform-specific antibodies, RD3 and RD4, are widely used for immunohistochemical and biochemical studies of tau species in diseased brains. Here, we show that extensive irreversible post-translational deamidation takes place at asparagine residue 279 (N279) in the RD4 epitope of tau in Alzheimer's disease (AD), but not corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP), and this modification abrogates the immunoreactivity to RD4. An antiserum raised against deamidated RD4 peptide specifically recognized 4R tau isoforms, regardless of deamidation, and strongly stained tau in AD brain. We also found that mutant tau with N279D substitution showed reduced ability to bind to microtubules and to promote microtubule assembly. The biochemical and structural differences of tau in AD from that in 4R tauopathies found in this study may therefore have implications for prion-like propagation of tau.
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