PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. AD pathology involves protein acetylation. Previous studies have mainly focused on histone acetylation in AD, however, the roles of nonhistone acetylation in AD are less explored.
The protein acetylation and expression levels were detected by western blotting and co-immunoprecipitation. The stoichiometry of acetylation was measured by home-made and site-specific antibodies against acetylated-CaM (Ac-CaM) at K22, K95, and K116. Hippocampus-dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests.
We showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+ /CaM-dependent kinase II α (CaMKIIα) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac-K22, K95-CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKIIα activity, and hippocampus-dependent memory in AD mice.
HDAC9-mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD.
The protein acetylation and expression levels were detected by western blotting and co-immunoprecipitation. The stoichiometry of acetylation was measured by home-made and site-specific antibodies against acetylated-CaM (Ac-CaM) at K22, K95, and K116. Hippocampus-dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests.
We showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+ /CaM-dependent kinase II α (CaMKIIα) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac-K22, K95-CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKIIα activity, and hippocampus-dependent memory in AD mice.
HDAC9-mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD.
摘要：
目的：阿尔茨海默病（AD）是一种以进行性认知功能障碍和记忆障碍为特征的神经退行性疾病。AD病理学涉及蛋白质乙酰化。以往的研究主要集中在AD的组蛋白乙酰化,然而,非组蛋白乙酰化在AD中的作用研究较少。
方法：通过蛋白质印迹和免疫共沉淀检测蛋白质乙酰化和表达水平。通过在K22，K95和K116处针对乙酰化CaM（Ac-CaM）的自制和位点特异性抗体来测量乙酰化的化学计量。使用Morris水迷宫评估海马依赖的学习和记忆，新颖的物体识别，和上下文恐惧条件测试。
结果：我们发现AD患者和小鼠血浆中的钙调蛋白（CaM）乙酰化降低。在AD小鼠脑中，CaM乙酰化及其靶Ca2/CaM依赖性激酶IIα（CaMKIIα）活性严重受损。化学计量显示,在AD患者和小鼠中,Ac-K22、K95-CaM乙酰化降低。此外，我们筛选并确定赖氨酸脱乙酰酶9（HDAC9）是CaM的主要脱乙酰酶。此外,HDAC9抑制增加CaM乙酰化和CaMKIIα活性，AD小鼠海马依赖性记忆。
结论：HDAC9介导的CaM去乙酰化诱导AD记忆障碍，HDAC9或CaM乙酰化可能成为AD的潜在治疗靶标。
方法：通过蛋白质印迹和免疫共沉淀检测蛋白质乙酰化和表达水平。通过在K22，K95和K116处针对乙酰化CaM（Ac-CaM）的自制和位点特异性抗体来测量乙酰化的化学计量。使用Morris水迷宫评估海马依赖的学习和记忆，新颖的物体识别，和上下文恐惧条件测试。
结果：我们发现AD患者和小鼠血浆中的钙调蛋白（CaM）乙酰化降低。在AD小鼠脑中，CaM乙酰化及其靶Ca2/CaM依赖性激酶IIα（CaMKIIα）活性严重受损。化学计量显示,在AD患者和小鼠中,Ac-K22、K95-CaM乙酰化降低。此外，我们筛选并确定赖氨酸脱乙酰酶9（HDAC9）是CaM的主要脱乙酰酶。此外,HDAC9抑制增加CaM乙酰化和CaMKIIα活性，AD小鼠海马依赖性记忆。
结论：HDAC9介导的CaM去乙酰化诱导AD记忆障碍，HDAC9或CaM乙酰化可能成为AD的潜在治疗靶标。
