Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease.
Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease.
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DOI：
10.1126/sciadv.abc8096
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发表时间：
2020-12
期刊：
影响因子：
13.6
通讯作者：
Yan Z
中科院分区：
文献类型：
--
作者：
Cao Q;Wang W;Williams JB;Yang F;Wang ZJ;Yan Z
本研究为AD及其相关疾病的治疗提供了新的表观遗传学机制和潜在的治疗策略。表观遗传畸变与衰老和神经退行性变有关。使用来自阿尔茨海默病（AD）患者和AD小鼠模型的死后组织，我们发现允许性组蛋白标记H3 K4 me 3及其催化酶在前额叶皮层（PFC）中显著升高。用化合物WDR 5 -0103抑制H3 K4特异性甲基转移酶导致AD小鼠PFC突触功能和记忆相关行为的实质性恢复。在AD小鼠PFC中通过WDR 5 -0103处理逆转的上调基因中，许多基因在其启动子处具有增加的H3 K4 me 3富集。其中一个已确定的顶级靶基因，Sgk 1，编码血清和糖皮质激素调节激酶1，也显着升高，在PFC的AD患者。给予特定的Sgk 1抑制剂可减少过度磷酸化的tau蛋白，恢复PFC介导的突触功能，并改善AD小鼠的记忆缺陷。这些结果为AD及相关神经退行性疾病的治疗提供了新的表观遗传学机制和潜在的治疗策略。
This study has found a novel epigenetic mechanism and a potential therapeutic strategy for AD and related diseases. Epigenetic aberration is implicated in aging and neurodegeneration. Using postmortem tissues from patients with Alzheimer’s disease (AD) and AD mouse models, we have found that the permissive histone mark H3K4me3 and its catalyzing enzymes are significantly elevated in the prefrontal cortex (PFC). Inhibiting H3K4-specific methyltransferases with the compound WDR5-0103 leads to the substantial recovery of PFC synaptic function and memory-related behaviors in AD mice. Among the up-regulated genes reversed by WDR5-0103 treatment in PFC of AD mice, many have the increased H3K4me3 enrichment at their promoters. One of the identified top-ranking target genes, Sgk1, which encodes serum and glucocorticoid-regulated kinase 1, is also significantly elevated in PFC of patients with AD. Administration of a specific Sgk1 inhibitor reduces hyperphosphorylated tau protein, restores PFC glutamatergic synaptic function, and ameliorates memory deficits in AD mice. These results have found a novel epigenetic mechanism and a potential therapeutic strategy for AD and related neurodegenerative disorders.
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影响因子：
25
作者：
Gan L;Cookson MR;Petrucelli L;La Spada AR
通讯作者：
La Spada AR
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
6.1
作者：
Koldamova, Radosveta;Schug, Jonathan;Lefterova, Martina;Cronican, Andrea A.;Fitz, Nicholas F.;Davenport, Faith A.;Carter, Alexis;Castranio, Emilie L.;Lefterov, Iliya
通讯作者：
Lefterov, Iliya
影响因子：
16.2
作者：
Bai, Bing;Wang, Xusheng;Peng, Junmin
通讯作者：
Peng, Junmin