Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits

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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Figure 1: Tau K174 is acetylated at early stages of AD.
Figure 2: K174Q leads to tau accumulation in vitro and in vivo.
Figure 3: Expression of K174Q tau induces neurodegeneration and cognitive deficits.
Figure 4: Salicylate inhibits p300 and reduces ac-K174 tau in cultured neurons and PS19 mice.
Figure 5: SSA treatment prevents hippocampal atrophy, reduces tau pathology and rescues spatial memory deficits in PS19 mice.
Figure 6: Tau-lowering and protective effects of SSA and salicylate involve ac-K174 inhibition.

References

  1. 1

    Ludolph, A.C. et al. Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options. Eur. J. Neurol. 16, 297–309 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    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).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  4. 4

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Ren, Y. & Sahara, N. Characteristics of tau oligomers. Frontiers Neurol. 4, 102 (2013).

    Google Scholar 

  6. 6

    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).

    CAS  PubMed  Google Scholar 

  7. 7

    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).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Berger, Z. et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J. Neurosci. 27, 3650–3662 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Sydow, A. et al. Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model. J. Mol. Neurosci. 45, 432–437 (2011).

    CAS  PubMed  Google Scholar 

  11. 11

    Wang, Y. & Mandelkow, E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644–652 (2012).

    CAS  PubMed  Google Scholar 

  12. 12

    Lee, B.H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Min, S.W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Cohen, T.J. et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2, 252 (2011).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Kim, G.W. & Yang, X.J. Comprehensive lysine acetylomes emerging from bacteria to humans. Trends Biochem. Sci. 36, 211–220 (2011).

    CAS  PubMed  Google Scholar 

  17. 17

    Mandelkow, E.M. & Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med. 2, a006247 (2012).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    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).

    CAS  PubMed  Google Scholar 

  19. 19

    Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

    CAS  PubMed  Google Scholar 

  20. 20

    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).

    CAS  PubMed  Google Scholar 

  21. 21

    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).

    CAS  PubMed  Google Scholar 

  22. 22

    Yeung, F. et al. Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD-dependent deacetylases. Oncogene 34, 798–804 (2015).

    CAS  PubMed  Google Scholar 

  23. 23

    Wang, B. et al. Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat. Commun. 5, 3479 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    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).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    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).

    PubMed  PubMed Central  Google Scholar 

  26. 26

    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).

    CAS  PubMed  Google Scholar 

  27. 27

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    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).

    CAS  PubMed  Google Scholar 

  31. 31

    Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    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).

    CAS  PubMed  Google Scholar 

  33. 33

    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).

    PubMed  PubMed Central  Google Scholar 

  34. 34

    Grinberg, L.T. et al. Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol. 125, 581–593 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Irwin, D.J. et al. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am. J. Pathol. 183, 344–351 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Irwin, D.J. et al. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies. Brain 135, 807–818 (2012).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    Morris, M. et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 18, 1183–1189 (2015).

    CAS  PubMed  Google Scholar 

  38. 38

    Smith, W.L., DeWitt, D.L. & Garavito, R.M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000).

    CAS  PubMed  Google Scholar 

  39. 39

    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).

    CAS  PubMed  Google Scholar 

  40. 40

    Aubry, S. et al. Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression. PLoS ONE 10, e0120352 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 41

    Hawley, S.A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    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).

    CAS  PubMed  Google Scholar 

  43. 43

    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).

    CAS  PubMed  Google Scholar 

  44. 44

    Greene, W.C. & Chen, L.F. Regulation of NF-κB action by reversible acetylation. Novartis Found. Symp. 259, 208–217 discussion 218–225 (2004).

    CAS  PubMed  Google Scholar 

  45. 45

    Lee, H. et al. Ethanol selectively modulates inflammatory activation signaling of brain microglia. J. Neuroimmunol. 156, 88–95 (2004).

    CAS  PubMed  Google Scholar 

  46. 46

    Apostolova, L.G. et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch. Neurol. 63, 693–699 (2006).

    PubMed  Google Scholar 

  47. 47

    Kerchner, G.A. et al. Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI. Neurology 75, 1381–1387 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Leung, K.K. et al. Cerebral atrophy in mild cognitive impairment and Alzheimer disease: rates and acceleration. Neurology 80, 648–654 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Reagan-Shaw, S., Nihal, M. & Ahmad, N. Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2008).

    CAS  PubMed  Google Scholar 

  50. 50

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    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).

    CAS  PubMed  Google Scholar 

  52. 52

    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).

    CAS  PubMed  Google Scholar 

  53. 53

    Pagans, S. et al. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 3, e41 (2005).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    Chen, J. et al. SIRT1 Protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364–40374 (2005).

    CAS  PubMed  Google Scholar 

  55. 55

    Barghorn, S. et al. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39, 11714–11721 (2000).

    CAS  PubMed  Google Scholar 

  56. 56

    Moore, C.L. et al. Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation. Biochemistry 50, 10876–10886 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Winsor, C.P. The Gompertz curve as a growth curve. Proc. Natl. Acad. Sci. USA 18, 1–8 (1932).

    CAS  PubMed  Google Scholar 

  58. 58

    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).

    CAS  PubMed  Google Scholar 

  59. 59

    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).

    CAS  PubMed  Google Scholar 

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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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Correspondence to Eric Verdin or Li Gan.

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The authors declare no competing financial interests.

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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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