Limits...
Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against A β toxicity in a mouse model of Alzheimer's disease

View Article: PubMed Central - PubMed

ABSTRACT

Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD.

No MeSH data available.


Related in: MedlinePlus

HDAC1 SUMOylation reduces amyloid plaque and the number of apoptotic cells in APP/PS1 mice. APP/PS1 mice (9 months old) receiving lenti-vector, lenti-Flag-HDAC1WT vector or lenti-Flag-HDAC1WT-SUMO1 vector, and WT mice receiving lenti-vector tranductions were subjected to (a) immunohistochemistry with antibody against Aβ and thioflavin S staining were carried out in CA1 tissue of APP/PS1 mice (9 months old) (n=3). Scale bar, 100 μm. (b) Immunohistochemistry with antibody against Aβ and ProteoStat dye staining were carried out in the same mice (n=3). Scale bar, 100 μm. Animals receiving the same lenti-vector transductions described in Figure 5a were also subjected to (c) thioflavin S staining and quantified (n=4 each group; F3,12=80.81, P<0.001). Arrowheads indicate cells showing thioflavin S staining. Scale bar, 200 μm and (d) ProteoStat dye staining and quantified (n=4 each group; F3,12=201.15, P<0.001). Arrowheads indicate cells showing ProteoStat dye staining. Scale bar, 200 μm and (e) TUNEL staining and quantified (n=4 each group; F3,12=60.4, P<0.001). Cells in brown color indicated by arrowheads are the apoptotic cells. Scale bar, 50 μm. (f) Flag-vector, Flag-HDAC1WT plasmid, Flag-HDAC1 sumo-mutant plasmid or Flag-HDAC1-SUMO1 fusion plasmid was transfected to rat CA1 area and ChIP PCR for HDAC1 binding to the neprilysin promoter was determined. Plasmid transfection and expression was confirmed by immunoprecipitation and immunoblotting using anti-Flag antibody (lower panel). Experiments are in duplicates. Lenti-F-HDAC1WT: Lenti-Flag-HDAC1WT. Data are mean±s.e.m. #P<0.001
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384022&req=5

fig6: HDAC1 SUMOylation reduces amyloid plaque and the number of apoptotic cells in APP/PS1 mice. APP/PS1 mice (9 months old) receiving lenti-vector, lenti-Flag-HDAC1WT vector or lenti-Flag-HDAC1WT-SUMO1 vector, and WT mice receiving lenti-vector tranductions were subjected to (a) immunohistochemistry with antibody against Aβ and thioflavin S staining were carried out in CA1 tissue of APP/PS1 mice (9 months old) (n=3). Scale bar, 100 μm. (b) Immunohistochemistry with antibody against Aβ and ProteoStat dye staining were carried out in the same mice (n=3). Scale bar, 100 μm. Animals receiving the same lenti-vector transductions described in Figure 5a were also subjected to (c) thioflavin S staining and quantified (n=4 each group; F3,12=80.81, P<0.001). Arrowheads indicate cells showing thioflavin S staining. Scale bar, 200 μm and (d) ProteoStat dye staining and quantified (n=4 each group; F3,12=201.15, P<0.001). Arrowheads indicate cells showing ProteoStat dye staining. Scale bar, 200 μm and (e) TUNEL staining and quantified (n=4 each group; F3,12=60.4, P<0.001). Cells in brown color indicated by arrowheads are the apoptotic cells. Scale bar, 50 μm. (f) Flag-vector, Flag-HDAC1WT plasmid, Flag-HDAC1 sumo-mutant plasmid or Flag-HDAC1-SUMO1 fusion plasmid was transfected to rat CA1 area and ChIP PCR for HDAC1 binding to the neprilysin promoter was determined. Plasmid transfection and expression was confirmed by immunoprecipitation and immunoblotting using anti-Flag antibody (lower panel). Experiments are in duplicates. Lenti-F-HDAC1WT: Lenti-Flag-HDAC1WT. Data are mean±s.e.m. #P<0.001

Mentions: The brains of AD patients and in mouse model of AD are characterized by amyloid plaque accumulation followed by neuronal death. Next, we examined whether HDAC1 SUMOylation has a rescuing effect against these pathologies in APP/PS1 mice. Different APP/PS1 mice were used for this purpose. Antibody against Aβ was used to detect the presence of Aβ and thioflavin S staining was used to detect Aβ aggregation and amyloid plaque formation. Results from immunohistochemistry indicated the presence of Aβ (Figure 6a, left panel) and amyloid plaque (Figure 6a, middle panel) in the CA1 area of APP/PS1 mice, and these two images overlapped (Figure 6a, right panel). ProteoStat dye staining was also used to confirm the presence of amyloid plaque and its co-localization with Aβ in the same area (Figure 6b). Further immunohistochemical results of thioflavin-S staining revealed that transduction of lenti-Flag-HDAC1WT vector to APP/PS1 mice showed slightly higher amount of amyloid plaque, as indicated by the arrowheads, as that of APP/PS1 mice receiving lenti-vector transduction (Figure 6c, lower-left panel versus upper-right panel), but amyloid plaque was significantly reduced in APP/PS1 mice receiving lenti-Flag-HDAC1WT-SUMO1 vector transduction compared with APP/PS1 mice receiving lenti-vector transduction (Figure 6c, lower-right panel versus upper-right panel). The quantified result is shown in the right panel. Similar results were obtained when ProteoStat dye staining was used as a measure of amyloid plaque (Figure 6d). Moreover, lenti-Flag-HDAC1WT-SUMO1 vector transduction also showed a rescuing effect in reducing amyloid plaque in older APP/PS1 mice (12 months old), but this effect was less significant due to more amyloid plaque formation in animals at this age (Supplementary Figure S6).


Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against A β toxicity in a mouse model of Alzheimer's disease
HDAC1 SUMOylation reduces amyloid plaque and the number of apoptotic cells in APP/PS1 mice. APP/PS1 mice (9 months old) receiving lenti-vector, lenti-Flag-HDAC1WT vector or lenti-Flag-HDAC1WT-SUMO1 vector, and WT mice receiving lenti-vector tranductions were subjected to (a) immunohistochemistry with antibody against Aβ and thioflavin S staining were carried out in CA1 tissue of APP/PS1 mice (9 months old) (n=3). Scale bar, 100 μm. (b) Immunohistochemistry with antibody against Aβ and ProteoStat dye staining were carried out in the same mice (n=3). Scale bar, 100 μm. Animals receiving the same lenti-vector transductions described in Figure 5a were also subjected to (c) thioflavin S staining and quantified (n=4 each group; F3,12=80.81, P<0.001). Arrowheads indicate cells showing thioflavin S staining. Scale bar, 200 μm and (d) ProteoStat dye staining and quantified (n=4 each group; F3,12=201.15, P<0.001). Arrowheads indicate cells showing ProteoStat dye staining. Scale bar, 200 μm and (e) TUNEL staining and quantified (n=4 each group; F3,12=60.4, P<0.001). Cells in brown color indicated by arrowheads are the apoptotic cells. Scale bar, 50 μm. (f) Flag-vector, Flag-HDAC1WT plasmid, Flag-HDAC1 sumo-mutant plasmid or Flag-HDAC1-SUMO1 fusion plasmid was transfected to rat CA1 area and ChIP PCR for HDAC1 binding to the neprilysin promoter was determined. Plasmid transfection and expression was confirmed by immunoprecipitation and immunoblotting using anti-Flag antibody (lower panel). Experiments are in duplicates. Lenti-F-HDAC1WT: Lenti-Flag-HDAC1WT. Data are mean±s.e.m. #P<0.001
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384022&req=5

fig6: HDAC1 SUMOylation reduces amyloid plaque and the number of apoptotic cells in APP/PS1 mice. APP/PS1 mice (9 months old) receiving lenti-vector, lenti-Flag-HDAC1WT vector or lenti-Flag-HDAC1WT-SUMO1 vector, and WT mice receiving lenti-vector tranductions were subjected to (a) immunohistochemistry with antibody against Aβ and thioflavin S staining were carried out in CA1 tissue of APP/PS1 mice (9 months old) (n=3). Scale bar, 100 μm. (b) Immunohistochemistry with antibody against Aβ and ProteoStat dye staining were carried out in the same mice (n=3). Scale bar, 100 μm. Animals receiving the same lenti-vector transductions described in Figure 5a were also subjected to (c) thioflavin S staining and quantified (n=4 each group; F3,12=80.81, P<0.001). Arrowheads indicate cells showing thioflavin S staining. Scale bar, 200 μm and (d) ProteoStat dye staining and quantified (n=4 each group; F3,12=201.15, P<0.001). Arrowheads indicate cells showing ProteoStat dye staining. Scale bar, 200 μm and (e) TUNEL staining and quantified (n=4 each group; F3,12=60.4, P<0.001). Cells in brown color indicated by arrowheads are the apoptotic cells. Scale bar, 50 μm. (f) Flag-vector, Flag-HDAC1WT plasmid, Flag-HDAC1 sumo-mutant plasmid or Flag-HDAC1-SUMO1 fusion plasmid was transfected to rat CA1 area and ChIP PCR for HDAC1 binding to the neprilysin promoter was determined. Plasmid transfection and expression was confirmed by immunoprecipitation and immunoblotting using anti-Flag antibody (lower panel). Experiments are in duplicates. Lenti-F-HDAC1WT: Lenti-Flag-HDAC1WT. Data are mean±s.e.m. #P<0.001
Mentions: The brains of AD patients and in mouse model of AD are characterized by amyloid plaque accumulation followed by neuronal death. Next, we examined whether HDAC1 SUMOylation has a rescuing effect against these pathologies in APP/PS1 mice. Different APP/PS1 mice were used for this purpose. Antibody against Aβ was used to detect the presence of Aβ and thioflavin S staining was used to detect Aβ aggregation and amyloid plaque formation. Results from immunohistochemistry indicated the presence of Aβ (Figure 6a, left panel) and amyloid plaque (Figure 6a, middle panel) in the CA1 area of APP/PS1 mice, and these two images overlapped (Figure 6a, right panel). ProteoStat dye staining was also used to confirm the presence of amyloid plaque and its co-localization with Aβ in the same area (Figure 6b). Further immunohistochemical results of thioflavin-S staining revealed that transduction of lenti-Flag-HDAC1WT vector to APP/PS1 mice showed slightly higher amount of amyloid plaque, as indicated by the arrowheads, as that of APP/PS1 mice receiving lenti-vector transduction (Figure 6c, lower-left panel versus upper-right panel), but amyloid plaque was significantly reduced in APP/PS1 mice receiving lenti-Flag-HDAC1WT-SUMO1 vector transduction compared with APP/PS1 mice receiving lenti-vector transduction (Figure 6c, lower-right panel versus upper-right panel). The quantified result is shown in the right panel. Similar results were obtained when ProteoStat dye staining was used as a measure of amyloid plaque (Figure 6d). Moreover, lenti-Flag-HDAC1WT-SUMO1 vector transduction also showed a rescuing effect in reducing amyloid plaque in older APP/PS1 mice (12 months old), but this effect was less significant due to more amyloid plaque formation in animals at this age (Supplementary Figure S6).

View Article: PubMed Central - PubMed

ABSTRACT

Amyloid-&beta; (A&beta;) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on A&beta; insult is less well known. Here we found that acute A&beta; increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and A&beta; induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks A&beta; induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates A&beta; induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against A&beta; toxicity and provide an alternative therapeutic strategy against AD.

No MeSH data available.


Related in: MedlinePlus