Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL 60611, USA.
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL 60611, USA.
Brain Res. 2024 Aug 15;1837:148951. doi: 10.1016/j.brainres.2024.148951. Epub 2024 Apr 18.
Epigenetics plays a vital role in aging and Alzheimer's disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, using 3-, 12- and 18- month-old APP/PS1 mice and age matched WT littermates, we conducted a series of memory tests, measured synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters in the hippocampus and prefrontal cortex (PFC). Our results showed impaired recognition and long-term spatial memory in 18-month-old WT mice and impaired recognition, short-term working, and long-term spatial reference memory in 12-and 18- month-old APP/PS1 mice. These memory impairments are associated with changes of synapse-related gene (nr2a, glur1, glur2, psd95) expression, HDAC abundance, and H3K9ac levels; more specifically, increased HDAC2 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during aging and AD progression in the hippocampus. Conversely, increased HDAC3 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during AD progression in the PFC. These findings suggest memory impairments in aging and AD may associated with a differential HDAC modulation of synapse-related gene expression in the brain.
表观遗传学在衰老和阿尔茨海默病（AD）中起着至关重要的作用；然而，衰老过程中的表观遗传改变是否可以引发 AD 并加剧 AD 的进展尚不清楚。在这项研究中，我们使用了 3、12 和 18 个月大的 APP/PS1 小鼠和年龄匹配的 WT 同窝仔鼠，进行了一系列记忆测试，测量了海马体和前额叶皮层（PFC）中突触相关基因表达、class 1 组蛋白去乙酰化酶（HDACs）丰度以及靶基因启动子处 H3K9ac 水平。我们的结果显示，18 个月大的 WT 小鼠的识别和长期空间记忆受损，12 个月大和 18 个月大的 APP/PS1 小鼠的识别、短期工作和长期空间参考记忆受损。这些记忆损伤与突触相关基因（nr2a、glur1、glur2、psd95）表达、HDAC 丰度和 H3K9ac 水平的变化有关；更具体地说，HDAC2 的增加与通过在海马体衰老和 AD 进展过程中在基因启动子处调节 H3K9ac 引起的突触相关基因表达变化有关。相反，HDAC3 的增加与通过在 PFC 中 AD 进展过程中在基因启动子处调节 H3K9ac 引起的突触相关基因表达变化有关。这些发现表明，衰老和 AD 中的记忆损伤可能与大脑中突触相关基因表达的不同 HDAC 调节有关。
