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.


An illustration shows the relationship among Aβ, HDAC1 SUMOylation, HDAC1 association with CREB and other proteins in the repressor complex, CREB binding to the Mcl-1 promoter, Mcl-1 gene expression and HDAC1 binding to the neprilysin promoter in the hippocampus. This illustration also indicates that a few endogenous stimuli could activate HDAC1 SUMOylation in the brain
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: An illustration shows the relationship among Aβ, HDAC1 SUMOylation, HDAC1 association with CREB and other proteins in the repressor complex, CREB binding to the Mcl-1 promoter, Mcl-1 gene expression and HDAC1 binding to the neprilysin promoter in the hippocampus. This illustration also indicates that a few endogenous stimuli could activate HDAC1 SUMOylation in the brain

Mentions: In summary, we have presently found that HDAC1 could be SUMO-modified by PIAS1 at Lys-444 and Lys-476. Acute Aβ-treatment significantly increases the level of HDAC1 SUMOylation in the hippocampus through MAPK/ERK-mediated signaling at 1 h, but not 14 days later. Enhanced HDAC1 SUMOylation decreases its association with CREB, increases CREB binding to the Mcl-1 promoter and increases Mcl-1 expression. HDAC1 SUMOylation also decreases HDAC1 binding to the neprilysin promoter (Figure 7). These mechanisms together reduce the number of apoptotic cells and the amount of amyloid plaque in the CA1 area of APP/PS1 mice. These mechanisms also rescue the cognitive impairment and synaptic deficit in APP/PS1 mice. Thus, HDAC1 SUMOylation functions as an endogenous defense mechanism protecting against Aβ-toxicity. Stimuli such as BDNF, IGF-1 and CRF that increase the level of HDAC1 SUMOylation without altering the HDAC1 expression level may serve as an alternative therapeutic strategy against AD.


Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against A β toxicity in a mouse model of Alzheimer's disease
An illustration shows the relationship among Aβ, HDAC1 SUMOylation, HDAC1 association with CREB and other proteins in the repressor complex, CREB binding to the Mcl-1 promoter, Mcl-1 gene expression and HDAC1 binding to the neprilysin promoter in the hippocampus. This illustration also indicates that a few endogenous stimuli could activate HDAC1 SUMOylation in the brain
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: An illustration shows the relationship among Aβ, HDAC1 SUMOylation, HDAC1 association with CREB and other proteins in the repressor complex, CREB binding to the Mcl-1 promoter, Mcl-1 gene expression and HDAC1 binding to the neprilysin promoter in the hippocampus. This illustration also indicates that a few endogenous stimuli could activate HDAC1 SUMOylation in the brain
Mentions: In summary, we have presently found that HDAC1 could be SUMO-modified by PIAS1 at Lys-444 and Lys-476. Acute Aβ-treatment significantly increases the level of HDAC1 SUMOylation in the hippocampus through MAPK/ERK-mediated signaling at 1 h, but not 14 days later. Enhanced HDAC1 SUMOylation decreases its association with CREB, increases CREB binding to the Mcl-1 promoter and increases Mcl-1 expression. HDAC1 SUMOylation also decreases HDAC1 binding to the neprilysin promoter (Figure 7). These mechanisms together reduce the number of apoptotic cells and the amount of amyloid plaque in the CA1 area of APP/PS1 mice. These mechanisms also rescue the cognitive impairment and synaptic deficit in APP/PS1 mice. Thus, HDAC1 SUMOylation functions as an endogenous defense mechanism protecting against Aβ-toxicity. Stimuli such as BDNF, IGF-1 and CRF that increase the level of HDAC1 SUMOylation without altering the HDAC1 expression level may serve as an alternative therapeutic strategy against AD.

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.