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Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schlüter OM, Bradke F, Lu J, Fischer A - EMBO Mol Med (2012)

Bottom Line: However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood.Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking.Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.

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Loss of Hdac6 rescues Aβ-induced impairment of mitochondrial traffickingADDL, Aβ-derived diffusible ligand; py, hippocampal CA1 pyramidal cell layer; str. rad. Hippocampal stratum radiatum layer, DG, dentate gyrus; ACC, anterior cingulate cortex. Values are mean ± SEM. *p = 0.0112, ***p < 0.0001, analysed by Student's t-test.Left panel: Representative confocal microscopy images showing immunoreactivity against Aβ in the hippocampus and cortex of APPPS1-21 (n = 6) and APPPS1-21-Hdac6−/− mice (n = 7). Scale bar: 100 µm. Right panel: Corresponding quantification of Aβ plaque load.Representative immunoblot (upper) and quantitative analysis (lower) showing reduced levels of α-tubulin K40 acetylation in APPPS1-21 mice compared to wild type animals (n = 6, Student's t-test, p = 0.0024).Representative immunoblot (upper) and quantitative analysis (lower) showing increased levels of HDAC6 in APPPS1-21 mice compared to wild type animals (n = 4, Student's t-test, p = 0.0212).Representative immunoblot (upper) and corresponding quantification (lower) showing increased levels of α-tubulin K40ac in the hippocampus of APPPS1-21-Hdac6−/− compared to APPPS1-21 mice (n = 4, Student's t-test, p = 0.0007).Quantitative analysis depicting the distribution of mitochondrial trafficking at a distinct speed in primary hippocampal neurons isolated from Hdac6−/− and wild type mice.Percentage of motile mitochondria out of total mitochondria in the experiment described under (E).Experimental design. Primary hippocampal neurons from Hdac6−/− and wild type littermates were treated with ADDL for 30 or 60 min and mitochondrial trafficking was analysed.Upper panel: Representative time lapse images showing moving mitochondria in ADDL treated wild type and Hdac6−/− neurons before (0 min) and 30 or 60 min after treatment. Scale bar: 5 µm. Lower panel: Quantitative analysis shows ADDL-mediated impairment in mitochondrial trafficking in wild type (0 min vs. 30 or 60 min) but not in Hdac6−/− neurons (n = 6, Student's t-test, **p = 0.0053).Left panel: Representative images showing Tom20 and tubulinK40ac immunoreactivity in the hippocampus of wild type (n = 8), APPPS1-21 (n = 10) and APPPS1-21_HDAC6−/− mice (n = 18). Dashed lines indicate areas used for quantification. Scale bar: 50 µm for low magnification images and 10 µm for Tom20 high magnification images (high-mag.). Right panel: Quantification of Tom20 immunoreactivity displayed as the ratio of intensity in soma to that in str. rad.
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fig04: Loss of Hdac6 rescues Aβ-induced impairment of mitochondrial traffickingADDL, Aβ-derived diffusible ligand; py, hippocampal CA1 pyramidal cell layer; str. rad. Hippocampal stratum radiatum layer, DG, dentate gyrus; ACC, anterior cingulate cortex. Values are mean ± SEM. *p = 0.0112, ***p < 0.0001, analysed by Student's t-test.Left panel: Representative confocal microscopy images showing immunoreactivity against Aβ in the hippocampus and cortex of APPPS1-21 (n = 6) and APPPS1-21-Hdac6−/− mice (n = 7). Scale bar: 100 µm. Right panel: Corresponding quantification of Aβ plaque load.Representative immunoblot (upper) and quantitative analysis (lower) showing reduced levels of α-tubulin K40 acetylation in APPPS1-21 mice compared to wild type animals (n = 6, Student's t-test, p = 0.0024).Representative immunoblot (upper) and quantitative analysis (lower) showing increased levels of HDAC6 in APPPS1-21 mice compared to wild type animals (n = 4, Student's t-test, p = 0.0212).Representative immunoblot (upper) and corresponding quantification (lower) showing increased levels of α-tubulin K40ac in the hippocampus of APPPS1-21-Hdac6−/− compared to APPPS1-21 mice (n = 4, Student's t-test, p = 0.0007).Quantitative analysis depicting the distribution of mitochondrial trafficking at a distinct speed in primary hippocampal neurons isolated from Hdac6−/− and wild type mice.Percentage of motile mitochondria out of total mitochondria in the experiment described under (E).Experimental design. Primary hippocampal neurons from Hdac6−/− and wild type littermates were treated with ADDL for 30 or 60 min and mitochondrial trafficking was analysed.Upper panel: Representative time lapse images showing moving mitochondria in ADDL treated wild type and Hdac6−/− neurons before (0 min) and 30 or 60 min after treatment. Scale bar: 5 µm. Lower panel: Quantitative analysis shows ADDL-mediated impairment in mitochondrial trafficking in wild type (0 min vs. 30 or 60 min) but not in Hdac6−/− neurons (n = 6, Student's t-test, **p = 0.0053).Left panel: Representative images showing Tom20 and tubulinK40ac immunoreactivity in the hippocampus of wild type (n = 8), APPPS1-21 (n = 10) and APPPS1-21_HDAC6−/− mice (n = 18). Dashed lines indicate areas used for quantification. Scale bar: 50 µm for low magnification images and 10 µm for Tom20 high magnification images (high-mag.). Right panel: Quantification of Tom20 immunoreactivity displayed as the ratio of intensity in soma to that in str. rad.

Mentions: Preservation of associative and spatial memory function by reducing Hdac6 is likely to involve multiple cellular processes. To better understand the mechanisms underlying the effect of HDAC6 on memory function in APPPS1-21 mice, we first analysed Aβ plaque load in APPPS1-21 and APPPS1-21-Hdac6−/− mice. Immunohistochemical analysis revealed no difference between the two groups (Fig 4A). Taking into account that disturbances in cytoskeletal integrity play an important role during AD pathogenesis (Stokin et al, 2005), and that one of the best-described roles of HDAC6 is deacetylation of α-tubulin K40ac (Haggarty et al, 2003; Hubbert et al, 2002), we decided to analyze tubulin acetylation in APPPS1-21 and APPPS1-21-Hdac6−/− mice.


Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schlüter OM, Bradke F, Lu J, Fischer A - EMBO Mol Med (2012)

Loss of Hdac6 rescues Aβ-induced impairment of mitochondrial traffickingADDL, Aβ-derived diffusible ligand; py, hippocampal CA1 pyramidal cell layer; str. rad. Hippocampal stratum radiatum layer, DG, dentate gyrus; ACC, anterior cingulate cortex. Values are mean ± SEM. *p = 0.0112, ***p < 0.0001, analysed by Student's t-test.Left panel: Representative confocal microscopy images showing immunoreactivity against Aβ in the hippocampus and cortex of APPPS1-21 (n = 6) and APPPS1-21-Hdac6−/− mice (n = 7). Scale bar: 100 µm. Right panel: Corresponding quantification of Aβ plaque load.Representative immunoblot (upper) and quantitative analysis (lower) showing reduced levels of α-tubulin K40 acetylation in APPPS1-21 mice compared to wild type animals (n = 6, Student's t-test, p = 0.0024).Representative immunoblot (upper) and quantitative analysis (lower) showing increased levels of HDAC6 in APPPS1-21 mice compared to wild type animals (n = 4, Student's t-test, p = 0.0212).Representative immunoblot (upper) and corresponding quantification (lower) showing increased levels of α-tubulin K40ac in the hippocampus of APPPS1-21-Hdac6−/− compared to APPPS1-21 mice (n = 4, Student's t-test, p = 0.0007).Quantitative analysis depicting the distribution of mitochondrial trafficking at a distinct speed in primary hippocampal neurons isolated from Hdac6−/− and wild type mice.Percentage of motile mitochondria out of total mitochondria in the experiment described under (E).Experimental design. Primary hippocampal neurons from Hdac6−/− and wild type littermates were treated with ADDL for 30 or 60 min and mitochondrial trafficking was analysed.Upper panel: Representative time lapse images showing moving mitochondria in ADDL treated wild type and Hdac6−/− neurons before (0 min) and 30 or 60 min after treatment. Scale bar: 5 µm. Lower panel: Quantitative analysis shows ADDL-mediated impairment in mitochondrial trafficking in wild type (0 min vs. 30 or 60 min) but not in Hdac6−/− neurons (n = 6, Student's t-test, **p = 0.0053).Left panel: Representative images showing Tom20 and tubulinK40ac immunoreactivity in the hippocampus of wild type (n = 8), APPPS1-21 (n = 10) and APPPS1-21_HDAC6−/− mice (n = 18). Dashed lines indicate areas used for quantification. Scale bar: 50 µm for low magnification images and 10 µm for Tom20 high magnification images (high-mag.). Right panel: Quantification of Tom20 immunoreactivity displayed as the ratio of intensity in soma to that in str. rad.
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fig04: Loss of Hdac6 rescues Aβ-induced impairment of mitochondrial traffickingADDL, Aβ-derived diffusible ligand; py, hippocampal CA1 pyramidal cell layer; str. rad. Hippocampal stratum radiatum layer, DG, dentate gyrus; ACC, anterior cingulate cortex. Values are mean ± SEM. *p = 0.0112, ***p < 0.0001, analysed by Student's t-test.Left panel: Representative confocal microscopy images showing immunoreactivity against Aβ in the hippocampus and cortex of APPPS1-21 (n = 6) and APPPS1-21-Hdac6−/− mice (n = 7). Scale bar: 100 µm. Right panel: Corresponding quantification of Aβ plaque load.Representative immunoblot (upper) and quantitative analysis (lower) showing reduced levels of α-tubulin K40 acetylation in APPPS1-21 mice compared to wild type animals (n = 6, Student's t-test, p = 0.0024).Representative immunoblot (upper) and quantitative analysis (lower) showing increased levels of HDAC6 in APPPS1-21 mice compared to wild type animals (n = 4, Student's t-test, p = 0.0212).Representative immunoblot (upper) and corresponding quantification (lower) showing increased levels of α-tubulin K40ac in the hippocampus of APPPS1-21-Hdac6−/− compared to APPPS1-21 mice (n = 4, Student's t-test, p = 0.0007).Quantitative analysis depicting the distribution of mitochondrial trafficking at a distinct speed in primary hippocampal neurons isolated from Hdac6−/− and wild type mice.Percentage of motile mitochondria out of total mitochondria in the experiment described under (E).Experimental design. Primary hippocampal neurons from Hdac6−/− and wild type littermates were treated with ADDL for 30 or 60 min and mitochondrial trafficking was analysed.Upper panel: Representative time lapse images showing moving mitochondria in ADDL treated wild type and Hdac6−/− neurons before (0 min) and 30 or 60 min after treatment. Scale bar: 5 µm. Lower panel: Quantitative analysis shows ADDL-mediated impairment in mitochondrial trafficking in wild type (0 min vs. 30 or 60 min) but not in Hdac6−/− neurons (n = 6, Student's t-test, **p = 0.0053).Left panel: Representative images showing Tom20 and tubulinK40ac immunoreactivity in the hippocampus of wild type (n = 8), APPPS1-21 (n = 10) and APPPS1-21_HDAC6−/− mice (n = 18). Dashed lines indicate areas used for quantification. Scale bar: 50 µm for low magnification images and 10 µm for Tom20 high magnification images (high-mag.). Right panel: Quantification of Tom20 immunoreactivity displayed as the ratio of intensity in soma to that in str. rad.
Mentions: Preservation of associative and spatial memory function by reducing Hdac6 is likely to involve multiple cellular processes. To better understand the mechanisms underlying the effect of HDAC6 on memory function in APPPS1-21 mice, we first analysed Aβ plaque load in APPPS1-21 and APPPS1-21-Hdac6−/− mice. Immunohistochemical analysis revealed no difference between the two groups (Fig 4A). Taking into account that disturbances in cytoskeletal integrity play an important role during AD pathogenesis (Stokin et al, 2005), and that one of the best-described roles of HDAC6 is deacetylation of α-tubulin K40ac (Haggarty et al, 2003; Hubbert et al, 2002), we decided to analyze tubulin acetylation in APPPS1-21 and APPPS1-21-Hdac6−/− mice.

Bottom Line: However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood.Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking.Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.

Show MeSH
Related in: MedlinePlus