The debate continues about which key modifications turn tau into a neuron killer. This study by Min et al. provides support for an original hypothesis suggesting that acetylation of tau is a key event in its pathogenicity. Using two antibodies they have developed that are specific for acetylated tau, they confirm that tau is acetylated in cultured neuronal cells as well as in the brains of mouse AD models and AD patients. They provide compelling data indicating that acetylated tau is less prone to ubiquitination, thereby reducing its recycling and favoring its hyperphosphorylation. They then show that a deacetylase present in the brain, SIRT1, can effectively reduce the proportion of both acetylated and ser202-phosphorylated tau. Probably the most interesting aspect of their work is that they actually suggest that decreasing the acetylation of tau is a potential relevant therapeutic target for AD, and that activation of SIRT1 may actually do that.

The connection between SIRT1 and AD has received much attention lately, suggesting that SIRT1 activation might represent a...  Read more

The debate continues about which key modifications turn tau into a neuron killer. This study by Min et al. provides support for an original hypothesis suggesting that acetylation of tau is a key event in its pathogenicity. Using two antibodies they have developed that are specific for acetylated tau, they confirm that tau is acetylated in cultured neuronal cells as well as in the brains of mouse AD models and AD patients. They provide compelling data indicating that acetylated tau is less prone to ubiquitination, thereby reducing its recycling and favoring its hyperphosphorylation. They then show that a deacetylase present in the brain, SIRT1, can effectively reduce the proportion of both acetylated and ser202-phosphorylated tau. Probably the most interesting aspect of their work is that they actually suggest that decreasing the acetylation of tau is a potential relevant therapeutic target for AD, and that activation of SIRT1 may actually do that.

The connection between SIRT1 and AD has received much attention lately, suggesting that SIRT1 activation might represent a potential therapeutic target (Gan and Mucke, 2008; Guarente and Picard, 2005; Lavu et al., 2008). This was firstly based on the discovery that SIRT1 played a critical role in the beneficial effect of calorie restriction against aging processes (Gan and Mucke, 2008; Guarente and Picard, 2005). In vitro and in vivo evidence suggest that increased neuronal SIRT1 activity leads to attenuation of amyloid pathology through regulation of the serine/threonine kinase ROCK1 and elevated α-secretase activity (Qin et al., 2006a; Qin et al., 2006b; Donmez et al., 2010). The link with tau is more recent and also more controversial. In support of such a link, we have recently found that postmortem levels of SIRT1 were correlated with ante-mortem cognitive status and to the extent of tau neuropathology (Julien et al., 2009). However, data from LaFerla’s group show that SIRT1 genetic knockdown leads instead to reduced Thr231-phosphorylated tau (Green et al., 2008), in sharp contrast with data from Min et al.

In summary, these exciting new data provide additional support for the development of brain-penetrant SIRT1 activators that are more potent and more selective than resveratrol (Feige et al., 2008; Lavu et al., 2008) or other tau-specific deacetylases.

References:
Donmez G, Wang D, Cohen DE, Guarente L (2010) SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 142: 320-332. Abstract

Feige J, Lagouge M, Canto C, Strehle A, Houten S, Milne J, Lambert P, Mataki C, Elliott P, Auwerx J (2008) Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation. Cell Metab 8: 347-358. Abstract

Gan L, Mucke L (2008) Paths of convergence: sirtuins in aging and neurodegeneration. Neuron 58: 10-14. Abstract

Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM (2008) Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 28: 11500-11510. Abstract

Guarente L, Picard F (2005) Calorie restriction--the SIR2 connection. Cell 120: 473-482. Abstract

Julien C, Tremblay C, Emond V, Lebbadi M, Salem NJ, Bennett DA, Calon F (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68: 48-58. Abstract

Lavu S, Boss O, Elliott PJ, Lambert PD (2008) Sirtuins--novel therapeutic targets to treat age-associated diseases. Nat Rev Drug Discov 7: 841-853. Abstract

Qin W, Chachich M, Lane M, Roth G, Bryant M, de Cabo R, Ottinger MA, Mattison J, Ingram D, Gandy S, Pasinetti GM (2006a) Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J Alzheimers Dis 10: 417-422. Abstract

Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AAA, Pasinetti GM (2006b) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281: 21745-21754. Abstract

View all comments by Frederic Calon

This paper by Min et al. demonstrates that tau can be acetylated by the acetyltransferase p300/CBP, and that tau interacts with and is deacetylated by the Class III histone deacetylase Sirt1. The authors further show that after treatment of cells with MG132, which can inhibit the proteasome as well as lysosomal proteases (Lee and Goldberg 1998), levels of ubiquitinated tau increase with low doses of the Sirt1 inhibitor Ex527 (1μM), but are reduced on treatment with higher (10-50μM) doses of the sirtuin inhibitor (see Figure 6E). They demonstrate that in cell culture these higher doses of Ex527 reduce clearance of tau, which they propose is due to reduction in tau ubiquitination, and they show that tau acetylation is elevated under pathological conditions. Further, they inhibit p300/CBP pharmacologically and show a reduction in toxic phospho-tau. They logically conclude that activation of Sirt1 or inhibition of p300/CBP may be useful therapeutically in the treatment of tauopathy.

Both the proteasome and the lysosome have been shown to degrade tau, and ubiquitin can target...  Read more

This paper by Min et al. demonstrates that tau can be acetylated by the acetyltransferase p300/CBP, and that tau interacts with and is deacetylated by the Class III histone deacetylase Sirt1. The authors further show that after treatment of cells with MG132, which can inhibit the proteasome as well as lysosomal proteases (Lee and Goldberg 1998), levels of ubiquitinated tau increase with low doses of the Sirt1 inhibitor Ex527 (1μM), but are reduced on treatment with higher (10-50μM) doses of the sirtuin inhibitor (see Figure 6E). They demonstrate that in cell culture these higher doses of Ex527 reduce clearance of tau, which they propose is due to reduction in tau ubiquitination, and they show that tau acetylation is elevated under pathological conditions. Further, they inhibit p300/CBP pharmacologically and show a reduction in toxic phospho-tau. They logically conclude that activation of Sirt1 or inhibition of p300/CBP may be useful therapeutically in the treatment of tauopathy.

Both the proteasome and the lysosome have been shown to degrade tau, and ubiquitin can target proteins for proteasomal as well as autophagic degradation (Wang, Martinez-Vicente et al. 2009; Korolchuk, Menzies et al. 2010). Clearance pathways can compensate for one another when one becomes impaired, and mechanisms of autophagic clearance in mammals are still being defined (Steffan 2010). Since multiple pathways of tau clearance exist, acetylation may activate tau clearance by one mechanism but reduce its clearance by another. We demonstrated that genetic reduction of Sirt1, or its pharmacologic inhibition with nicotinamide, can reduce phosphorylated tau levels in a triple transgenic mouse model of AD, and that nicotinamide treatment prevents cognitive deficits (Green, Steffan et al. 2008). Similarly, we found that phosphorylation/acetylation of Huntingtin (Htt), the protein mutated in Huntington’s Disease (HD), activates its clearance by the proteasome and lysosome–consistent with a previous observation by the laboratory of Dimitri Krainc that mutant Huntingtin acetylation regulates its clearance by macroautophagy (Jeong, Then et al. 2009; Thompson, Aiken et al. 2009).

Recently, nicotinamide was shown to substantially improve motor deficits in a mouse model of HD (Hathorn, Snyder-Keller et al. 2010). The data described by Min et al. do suggest that activation of SIRT1 and inhibition of p300/CBP may increase a mechanism of clearance of tau. This does not preclude the possibility that increased acetylation induced by histone deacetylase inhibitors (class I, II and III) may activate a second mechanism of tau clearance which may be very important in brain (Steffan 2010). HDAC inhibition has been widely shown to be useful in the treatment of neurodegeneration (Mai, Rotili et al. 2009). Min et al. themselves show increased ubiquitination of tau with 1μM Ex527 treatment, consistent with that level of Sirt1 inhibition activating tau clearance in their system.

While phosphorylated/acetylated tau may indeed be the toxic species in tauopathy, activation of the mechanism of modified tau clearance by inhibiting rather than activating Sirt1 early in disease progression has already been shown in vivo to be a successful therapeutic approach.

References:
Green, K. N., J. S. Steffan, et al. (2008). "Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau." J Neurosci 28(45): 11500-10. Abstract

Hathorn, T., A. Snyder-Keller, et al. (2010). "Nicotinamide improves motor deficits and upregulates PGC-1alpha and BDNF gene expression in a mouse model of Huntington's disease." Neurobiol Dis. Abstract

Jeong, H., F. Then, et al. (2009). "Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation." Cell 137: 60-72. Abstract

Korolchuk, V. I., F. M. Menzies, et al. (2010). "Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems." FEBS Lett 584(7): 1393-8. Abstract

Lee, D. H. and A. L. Goldberg (1998). "Proteasome inhibitors: valuable new tools for cell biologists." Trends Cell Biol 8(10): 397-403. Abstract

Mai, A., D. Rotili, et al. (2009). "Histone deacetylase inhibitors and neurodegenerative disorders: holding the promise." Curr Pharm Des 15(34): 3940-57. Abstract

Min, S. W., S. H. Cho, et al. (2010). "Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy." Neuron 67(6): 953-966. Abstract

Steffan, J. S. (2010). "Does Huntingtin play a role in selective macroautophagy?" Cell Cycle 9(17): 3401-3413. Abstract

Thompson, L. M., C. T. Aiken, et al. (2009). "IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome." J Cell Biol 187(7): 1083-99. Abstract

Wang, Y., M. Martinez-Vicente, et al. (2009). "Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing." Hum Mol Genet 18(21): 4153-70. Abstract

View all comments by Joan Steffan

From a single human gene, many different forms of tau protein could arise. Some of these forms come from alternative splicing of the nuclear RNA transcript, but other forms are the consequence of a post-translational modification—phosphorylation. Recently, an additional modification for tau protein has been indicated—acetylation (Min et al., 2010).

In the last issue of Nature Communications, the group of Virginia Lee has observed that tau acetylation takes place in a key residue, lysine 280, which plays a role in the interaction of tau with microtubules. This finding shows how acetylation could regulate one of the main tau functions—its interaction with microtubules—but the report also opens the door for future experiments. Cohen et al. reported that tau deacetylation could occur through histone deacetylase 6 (HDA6), a deacetylase that is inhibited by tau. This hints that tau protein could self-regulate its deacetylation. This could be tested in the future. Secondly, it remains to be determined if acetylated tau could be deacetylated by more than one deacetylase. Lastly, as...  Read more

From a single human gene, many different forms of tau protein could arise. Some of these forms come from alternative splicing of the nuclear RNA transcript, but other forms are the consequence of a post-translational modification—phosphorylation. Recently, an additional modification for tau protein has been indicated—acetylation (Min et al., 2010).

In the last issue of Nature Communications, the group of Virginia Lee has observed that tau acetylation takes place in a key residue, lysine 280, which plays a role in the interaction of tau with microtubules. This finding shows how acetylation could regulate one of the main tau functions—its interaction with microtubules—but the report also opens the door for future experiments. Cohen et al. reported that tau deacetylation could occur through histone deacetylase 6 (HDA6), a deacetylase that is inhibited by tau. This hints that tau protein could self-regulate its deacetylation. This could be tested in the future. Secondly, it remains to be determined if acetylated tau could be deacetylated by more than one deacetylase. Lastly, as indicated in this paper, tau-lysine 280 is present in a motif that is similar to those present in other microtubule-associated proteins like MAP2 or MAP4. Thus, acetylation could be a common mechanism to regulate the interaction of some MAPs with microtubules, as the authors have proposed.

In summary, this is an interesting and seminal work on the regulation of tau function.

References:
Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010 Sep 23;67(6):953-66. Abstract

View all comments by Jesus Avila