Abstract
Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.
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References
Ludolph, A.C. et al. Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options. Eur. J. Neurol. 16, 297–309 (2009).
Cairns, N.J. et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 114, 5–22 (2007).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Lasagna-Reeves, C.A. et al. Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J. 26, 1946–1959 (2012).
Ren, Y. & Sahara, N. Characteristics of tau oligomers. Frontiers Neurol. 4, 102 (2013).
Maeda, S. et al. Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer′s disease. Neurosci. Res. 54, 197–201 (2006).
Lasagna-Reeves, C.A. et al. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol. Neurodegener. 6, 39 (2011).
Berger, Z. et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J. Neurosci. 27, 3650–3662 (2007).
Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).
Sydow, A. et al. Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model. J. Mol. Neurosci. 45, 432–437 (2011).
Wang, Y. & Mandelkow, E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644–652 (2012).
Lee, B.H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010).
Tai, H.C. et al. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181, 1426–1435 (2012).
Min, S.W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010).
Cohen, T.J. et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2, 252 (2011).
Kim, G.W. & Yang, X.J. Comprehensive lysine acetylomes emerging from bacteria to humans. Trends Biochem. Sci. 36, 211–220 (2011).
Mandelkow, E.M. & Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med. 2, a006247 (2012).
Cook, C. et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum. Mol. Genet. 23, 104–116 (2014).
Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).
Jicha, G.A., Bowser, R., Kazam, I.G. & Davies, P. Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J. Neurosci. Res. 48, 128–132 (1997).
Weaver, C.L., Espinoza, M., Kress, Y. & Davies, P. Conformational change as one of the earliest alterations of tau in Alzheimer's disease. Neurobiol. Aging 21, 719–727 (2000).
Yeung, F. et al. Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD-dependent deacetylases. Oncogene 34, 798–804 (2015).
Wang, B. et al. Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat. Commun. 5, 3479 (2014).
Zhao, Y. et al. p300-dependent acetylation of activating transcription factor 5 enhances C/EBPβ transactivation of C/EBPα during 3T3–L1 differentiation. Mol. Cell. Biol. 34, 315–324 (2014).
Jaworski, T. et al. AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice. PLoS ONE 4, e7280 (2009).
Lecourtier, L. et al. Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral hippocampal lesion in rats. Neuroscience 207, 110–123 (2012).
Takeuchi, H. et al. P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS ONE 6, e21050 (2011).
Kasper, L.H. et al. CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation. EMBO J. 29, 3660–3672 (2010).
Kasper, L.H., Qu, C., Obenauer, J.C., McGoldrick, D.J. & Brindle, P.K. Genome-wide and single-cell analyses reveal a context dependent relationship between CBP recruitment and gene expression. Nucleic Acids Res. 42, 11363–11382 (2014).
Jin, Q. et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249–262 (2011).
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
Yoshiyama, Y., Kojima, A., Ishikawa, C. & Arai, K. Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model. J. Alzheimers Dis. 22, 295–306 (2010).
Faizi, M. et al. Thy1-hAPPLond/Swe+ mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain Behav. 2, 142–154 (2012).
Grinberg, L.T. et al. Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol. 125, 581–593 (2013).
Irwin, D.J. et al. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am. J. Pathol. 183, 344–351 (2013).
Irwin, D.J. et al. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies. Brain 135, 807–818 (2012).
Morris, M. et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 18, 1183–1189 (2015).
Smith, W.L., DeWitt, D.L. & Garavito, R.M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000).
in t' Veld, B.A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345, 1515–1521 (2001).
Aubry, S. et al. Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression. PLoS ONE 10, e0120352 (2015).
Hawley, S.A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).
Zhang, Y., Qiu, J., Wang, X., Zhang, Y. & Xia, M. AMP-activated protein kinase suppresses endothelial cell inflammation through phosphorylation of transcriptional coactivator p300. Arterioscler. Thromb. Vasc. Biol. 31, 2897–2908 (2011).
Lim, J.Y., Oh, M.A., Kim, W.H., Sohn, H.Y. & Park, S.I. AMP-activated protein kinase inhibits TGF-β-induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300. J. Cell. Physiol. 227, 1081–1089 (2012).
Greene, W.C. & Chen, L.F. Regulation of NF-κB action by reversible acetylation. Novartis Found. Symp. 259, 208–217 discussion 218–225 (2004).
Lee, H. et al. Ethanol selectively modulates inflammatory activation signaling of brain microglia. J. Neuroimmunol. 156, 88–95 (2004).
Apostolova, L.G. et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch. Neurol. 63, 693–699 (2006).
Kerchner, G.A. et al. Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI. Neurology 75, 1381–1387 (2010).
Leung, K.K. et al. Cerebral atrophy in mild cognitive impairment and Alzheimer disease: rates and acceleration. Neurology 80, 648–654 (2013).
Reagan-Shaw, S., Nihal, M. & Ahmad, N. Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2008).
Schilling, B. et al. Platform-independent and label-free quantitation of proteomic data using MS1 extracted ion chromatograms in skyline: application to protein acetylation and phosphorylation. Mol. Cell. Proteomics 11, 202–214 (2012).
Shilov, I.V. et al. The Paragon Algorithm, a next generation search engine that uses sequence temperature values and feature probabilities to identify peptides from tandem mass spectra. Mol. Cell. Proteomics 6, 1638–1655 (2007).
Perkins, D.N., Pappin, D.J., Creasy, D.M. & Cottrell, J.S. Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis 20, 3551–3567 (1999).
Pagans, S. et al. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 3, e41 (2005).
Chen, J. et al. SIRT1 Protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364–40374 (2005).
Barghorn, S. et al. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39, 11714–11721 (2000).
Moore, C.L. et al. Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation. Biochemistry 50, 10876–10886 (2011).
Winsor, C.P. The Gompertz curve as a growth curve. Proc. Natl. Acad. Sci. USA 18, 1–8 (1932).
Sun, A., Nguyen, X.V. & Bing, G. Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections. J. Histochem. Cytochem. 50, 463–472 (2002).
Kim, S.W. et al. Robust protective effects of a novel multimodal neuroprotectant oxopropanoyloxy benzoic acid (a salicylic acid/pyruvate ester) in the postischemic brain. Mol. Pharmacol. 79, 220–228 (2011).
Acknowledgements
We thank V. Haroutunian (The Icahn School of Medicine at Mount Sinai) and W.W. Seeley (UCSF) for human brain samples; B. Hann and J. Freimuth (UCSF) for oral gavage; L. Petrucelli (Mayo Clinic) for ac-KIGS antibody; P. Davies (Feinstein Institute for Medical Research) for MC1 and PHF-1 antibodies, Prothena Biosciences for 12E8 antibody; R. Ponnusamy and N. Devidze for advice on behavioral analyses; D. Song for PK analysis (PPL Inc); M. Finucane and S. Liu for advice on statistical analysis; L. Mucke and S. Meada for insightful discussions; L. Grinberg for technical advice on pathological analysis; C. Brennecka, G. Howard and S. Ordway for editorial review; J. Carroll and G. Maki for graphics assistance; E. Nguyen for administrative assistance and AB SCIEX for evaluation of the TripleTOF 5600 at the Buck Institute. This work was supported by a grant from the Tau Consortium (to L.G.) and US National Institutes of Health (NIH) grants 1R01AG036884 and R01AG030207 (to L.G.). We acknowledge the support of the NIH to L.E. (NIH NS40251 and NIH NS062413), and instrumentation from the NCRR shared instrumentation grant S10 RR024615 (to B.W.G.). Behavioral data were obtained with the help of the Gladstone Institutes' Neurobehavioral Core (supported by NIH grant P30NS065780).
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L.G., S.-W.M. and X.Chen. conceived the project. L.G., S.-W.M. and X.Chen. designed experiments. S.-W.M., X.Chen., T.E.T., P.D.S., S.A.M., C.W., K.S., S.S.M., E.D., B.S., X.Cong., J.J., Y.Z., Y.L. and E.M. performed experiments. L.E., B.W.G., M.S., J.G., N.K. and E.V. developed experimental tools or reagents. L.G., S.-W.M. and X.Chen. wrote the manuscript.
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Min, SW., Chen, X., Tracy, T. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21, 1154–1162 (2015). https://doi.org/10.1038/nm.3951
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DOI: https://doi.org/10.1038/nm.3951
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