Background: Cognitive capacities in Alzheimer’s Disease (AD) are impaired by an epigenetic blockade mediated by histone deacetylase 2 (HDAC2), which prevents the transcription of genes that are important for synaptic plasticity.

Objective: Investigation of the functional relationship between cell adhesion molecule L1 and HDAC2 in AD.

Methods: Cultures of dissociated cortical and hippocampal neurons from wild-type or L1-deficient mice were treated with Aβ1-42 for 24 h. After removal of Aβ1-42 cells were treated with the recombinant L1 extracellular domain (rL1) for 24 h followed by immunohistochemistry, western blotting, and reverse transcription PCR to evaluate the interaction between L1 and HDAC2.

Results: Aβ and HDAC2 protein levels were increased in APPSWE/L1+/- mutant brains compared to APPSWE mutant brains. Administration of the recombinant extracellular domain of L1 to cultured cortical and hippocampal neurons reduced HDAC2 mRNA and protein levels. In parallel, reduced phosphorylation levels of glucocorticoid receptor 1 (GR1), which is implicated in regulating HDAC2 levels, was observed in response to L1 administration. Application of a glucocorticoid receptor inhibitor reduced Aβ-induced GR1 phosphorylation and prevented the increase in HDAC2 levels. HDAC2 protein levels were increased in cultured cortical neurons from L1-deficient mice. This change could be reversed by the administration of the recombinant extracellular domain of L1.

Conclusion: Our results suggest that some functionally interdependent activities of L1 and HDAC2 contribute to ameliorating the phenotype of AD by GR1 dephosphorylation, which leads to reduced HDAC2 expression. The combined findings encourage further investigations on the beneficial effects of L1 in the treatment of AD.

背景：阿尔茨海默病 (AD) 的认知能力受到组蛋白去乙酰化酶 2 (HDAC2) 介导的表观遗传阻断的损害，这会阻止对突触可塑性很重要的基因的转录。

目的：研究AD中细胞粘附分子L1和HDAC2的功能关系。

方法：用 Aβ1-42 处理来自野生型或 L1 缺陷小鼠的分离的皮质和海马神经元培养物 24 小时。去除 Aβ1-42 后，细胞用重组 L1 细胞外结构域 (rL1) 处理 24 小时，然后进行免疫组织化学、蛋白质印迹和逆转录 PCR，以评估 L1 和 HDAC2 之间的相互作用。

结果：与 APPSWE 突变大脑相比，APPSWE/L1+/- 突变大脑中的 Aβ 和 HDAC2 蛋白水平增加。将 L1 的重组胞外域施用于培养的皮质和海马神经元可降低 HDAC2 mRNA 和蛋白质水平。同时，观察到与调节 HDAC2 水平有关的糖皮质激素受体 1 (GR1) 磷酸化水平降低，以响应 L1 给药。糖皮质激素受体抑制剂的应用降低了 Aβ 诱导的 GR1 磷酸化并阻止了 HDAC2 水平的增加。从 L1 缺陷小鼠培养的皮层神经元中 HDAC2 蛋白水平增加。这种变化可以通过施用 L1 的重组胞外域来逆转。

结论：我们的结果表明，L1 和 HDAC2 的一些功能上相互依赖的活动有助于通过 GR1 去磷酸化改善 AD 的表型，从而导致 HDAC2 表达降低。综合研究结果鼓励进一步研究 L1 在治疗 AD 中的有益作用。