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. 2018 Apr 11;38(15):3680-3688.
doi: 10.1523/JNEUROSCI.2369-17.2018. Epub 2018 Mar 14.

SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy

Sang-Won Min  1 , Peter Dongmin Sohn  1 , Yaqiao Li  1 , Nino Devidze  1 , Jeffrey R Johnson  2   3 , Nevan J Krogan  2   3 , Eliezer Masliah  4 , Sue-Ann Mok  5 , Jason E Gestwicki  6 , Li Gan  7   5
Affiliations

SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy

Sang-Won Min et al. J Neurosci. .

Erratum in

Abstract

Hyperacetylation of tau has been implicated in neurodegeneration and cognitive decline in tauopathy brains. The nicotinamide adenosine dinucleotide-dependent class-III protein deacetylase SIRT1 is one of the major enzymes involved in removal of acetyl groups from tau in vitro However, whether SIRT1 regulates acetylation of pathogenic tau and ameliorates tau-mediated pathogenesis remains unclear. Here, we report deacetylating activity of SIRT1 for acetylated Lys174 (K174) of tau in tauP301S transgenic mice with a brain-specific SIRT1 deletion. We show that SIRT1 deficiency leads to exacerbation of premature mortality, synapse loss, and behavioral disinhibition in tauP301S transgenic mice of both sexes. By contrast, SIRT1 overexpression by stereotaxic delivery of adeno-associated virus that encodes SIRT1 into the hippocampus reduces acetylated K174 tau. Furthermore, SIRT1 overexpression significantly attenuates the spread of tau pathology into anatomically connected brain regions of tauP301S transgenic mice of both sexes. These findings suggest the functional importance of SIRT1 in regulating pathogenic tau acetylation and in suppressing the spread of tau pathology in vivoSIGNIFICANCE STATEMENT In neurodegenerative disorders with inclusions of microtubule-associated protein tau, aberrant lysine acetylation of tau plays critical roles in promoting tau accumulation and toxicity. Identifying strategies to deacetylate tau could interfere with disease progression; however, little is known about how pathogenic tau is deacetylated in vivo Here we show that the protein deacetylase SIRT1 reduces tau acetylation in a mouse model of neurodegeneration. SIRT1 deficiency in the brain aggravates synapse loss and behavioral disinhibition, and SIRT1 overexpression ameliorates propagation of tau pathology.

Keywords: SIRT1; acetylation; dementia; tau; tau spread.

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Figures

Figure 1.
Figure 1.
SIRT1 reduces the levels of tau acetylation in vitro. A, Overexpression of SIRT1 significantly reduced p300-mediated tau acetylation in vitro. HEK293T cells were transfected with human 2N4R tau plasmid alone or cotransfected with p300 and/or SIRT1 plasmids. Western blot analysis was performed with a pan-ac-tau antibody (Ab708), pan-t-tau antibody (tau5), and tubulin antibody as a loading control. Representative images from three independent experiments. B, The SILAC system revealed downregulation of tau acetylation in multiple lysine sites. Mass spectrometry analyses identified a series of lysine sites of tau whose acetylation was decreased by overexpressing SIRT1. Ctrl:Ctrl compared heavy medium with expression of hTau, p300, and control vectors (Ctrl) with light medium with expression of hTau, p300, and control vectors (Ctrl). Ctrl:0.5 μg of SIRT1 compared heavy medium with expression of hTau, p300, and control vectors (Ctrl) with light medium with expression of hTau, p300, and 0.5 μg SIRT1 vectors (0.5 μg SIRT1). Ctrl:1.0 μg of SIRT1 compared heavy medium with expression of hTau, p300, and control vectors (Ctrl) with light medium with expression of hTau, p300, and 1.0 μg SIRT1 vectors (1.0 μg SIRT1). Log ratio was based on the peak of light medium normalized to the peak of heavy medium. −INF, Minus infinity log value due to no peak detection in light medium with SIRT1 expression.
Figure 2.
Figure 2.
Brain-specific deletion of SIRT1 in vivo selectively increases the levels of ac-K174 tau. A, B, Western blot of cortical lysates showed that deleting SIRT1 significantly increased the levels of ac-K174 tau, but not ac-K274 tau. A, Representative Western blot images from cortical lysates. Human tau was identified based on its distinct size of molecular weight that was larger than mouse tau. GAPDH was used as a loading control. B, Quantification showed a significant increase of human ac-K174 tau (AC312), but not human ac-K274 tau (MAB359) by SIRT1 deletion. n = 6–7 mice per genotype, ***p < 0.001, unpaired Student's t test. C, D, Western blot of PSD-enriched fractions showed that SIRT1 deletion increased the levels of ac-K174 tau as well as total tau. C, Representative Western blot images from PSD-enriched fractions. Robust expression of PSD-95 and GluA-1 along with the absence of synaptophysin expression indicated the enrichment of PSD fractions. D, Quantification of Western blot showed a significant increase of human ac-K174 tau (AC312) as well as human total tau (Tau5) in PSD-enriched fractions by SIRT1 deletion. n = 6–7 mice per genotype, *p < 0.05, unpaired Student's t test. Values are means ± SEM.
Figure 3.
Figure 3.
SIRT1 deletion exacerbates premature lethality and synapse loss in tauP301S mice. A, Kaplan–Meier survival analysis showed a significant reduction of survival rate in tauP301S mice with SIRT1 deletion than tauP301S mice without SIRT1 deletion. P301S−;Cre−, n = 19; P301S−;Cre+, n = 18; P301S+;Cre−, n = 18; P301S+;Cre+, n = 20. Log-rank (Mantel–Cox test), *p = 0.0329 (P301S+;Cre− vs P301S+;Cre+). B, C, Synapse loss was exacerbated in tauP301S mice with SIRT1 deletion. B, Synaptophysin (SY38) immunostaining in both the frontal cortex (FC) and hippocampus (HP). Scale bars: first row, 250 μm; second and third rows, 25 μm. C, Quantification of percentage of SY38-positive area showed a significant reduction of synapses in tauP301S mice with SIRT1 deletion. n = 6 mice per genotype, **p < 0.01, one-way ANOVA, Tukey's post hoc test. D, Formation of neurofibrillary tangle (NFT) was not altered in tauP301S mice with SIRT1 deletion. Gallyas silver staining was performed to investigate the degree of NFT in either tauP301S mice or tauP301S mice with SIRT1 deletion. No NFT was identified in tauP301S-negative mice as expected. n = 5–6 mice per genotype. Scale bars: first row, 250 μm; second row, 25 μm. Values are means ± SEM.
Figure 4.
Figure 4.
SIRT1 deletion leads to cognitive impairments in tauP301S mice. A, SIRT1 deletion exacerbated tau-mediated behavioral disinhibition in the EPM. P301S−;Cre−, n = 15; P301S−;Cre+, n = 15; P301S+;Cre−, n = 14; P301S+;Cre+, n = 10. ***p < 0.001, one-way ANOVA, Tukey's post hoc test. B, SIRT1 deletion led to tau-mediated spatial memory impairment in the small Y-maze. n = 10–11 mice per genotype. *p < 0.05, one-way ANOVA, Dunnett's post hoc test. C, D, SIRT1 deletion impaired spatial learning and memory in the Morris water maze test. n = 10–11 mice per genotype. C, SIRT1 deletion impaired spatial learning of locating a hidden platform. Swim speed did not differ between the groups. *p < 0.05, ***p < 0.001, multilevel mixed-effects model. D, SIRT1 deletion impaired memory retention in probe trials 24 h after learning. *p < 0.05; ***p < 0.001; paired Student's t test. Values are means ± SEM.
Figure 5.
Figure 5.
SIRT1 overexpression decreases the levels of ac-K174 tau and spreading of tau pathology in tauP301S mice. A, Schematic diagram of stereotaxic injections of AAV-GFP or AAV-SIRT1 and tau fibrils into the left and right hippocampus, respectively. B, Representative images of immunostaining with the flag antibody for visualization of SIRT1 expression in the hippocampus with AAV-GFP and AAV-SIRT1-Flag injections. C, D, Representative images and quantification of immunostaining of ac-K174 tau (AC312) in the mossy fiber of the hippocampus with AAV-GFP and AAV-SIRT1 injections. n = 10–11 mice per group. *p < 0.05, unpaired Student's t test. E, Representative images of MC1 immunostaining in the hippocampus with AAV-GFP and AAV-SIRT1 injections. Two rows on the top represented negative controls of nontransgenic (nTg) mice and tauP301S mice (Tg) without injection of tau fibrils. F, Quantification of MC1-positive area in the left (spread) and right (tau fibrils) sides of the hippocampus with AAV-GFP and AAV-SIRT1 injections. Percentage of MC1-positive area was analyzed, and then the ratio between left and right sides was calculated. n = 35–38 slices from 10 to 11 mice per group. **p < 0.01, multilevel mixed-effects model. Values are means ± SEM. Scale bars, 100 μm.
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Comment in

  • SIRT1: A Novel Way to Target Tau?
    Futch HS, Croft CL. Futch HS, et al. J Neurosci. 2018 Sep 5;38(36):7755-7757. doi: 10.1523/JNEUROSCI.1201-18.2018. J Neurosci. 2018. PMID: 30185537 Free PMC article. No abstract available.

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