Memory impairment is the main feature of Alzheimer's disease (AD). Initial impairments originate in the temporal lobe area and propagate throughout the brain in a sequential manner. Epigenetic mechanisms, especially histone acetylation, regulate plasticity and memory processes. These may be dismantled during the disease. The aim of this work was to establish changes in the acetylation-associated pathway in two key brain regions affected in AD: the hippocampus and the F2 area of frontal cortex in end-stage AD patients and age-matched controls. We found that the F2 area was more affected than the hippocampus. Indeed, CREB-Binding Protein (CBP), P300/CBP-associated protein (PCAF), Histone Deacetylase 1 (HDAC1) and HDAC2 (but not HDAC3) levels were strongly decreased in F2 area of AD compared to controls patients, whereas only HDAC1 was decreased and CBP showed a downward trend in the hippocampus. At the histone level, we detected a substantial increase in total (H3 and H2B) histone levels in the frontal cortex, but these were decreased in nuclear extracts, pointing to a dysregulation in histone trafficking/catabolism in this brain region. Histone H3 acetylation levels were increased in cell nuclei mainly in the frontal cortex. These findings provide evidence for acetylation dysfunctions at the level of associated enzymes and of histones in AD brains, which may underlie transcriptional dysregulations and AD-related cognitive impairments. They further point to stronger dysregulations in the F2 area of the frontal cortex than in the hippocampus at an end-stage of the disease, suggesting a differential vulnerability and/or compensatory mechanisms efficiency towards epigenetic alterations.

中文翻译：

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阿尔茨海默病患者海马和额叶皮质组蛋白乙酰化通路失调

记忆障碍是阿尔茨海默病 (AD) 的主要特征。最初的损伤起源于颞叶区域，并以连续的方式在整个大脑中传播。表观遗传机制，尤其是组蛋白乙酰化，调节可塑性和记忆过程。这些可能在疾病期间被拆除。这项工作的目的是确定 AD 受影响的两个关键大脑区域中乙酰化相关通路的变化：AD 末期患者和年龄匹配对照的海马和额叶皮层的 F2 区域。我们发现 F2 区域比海马体受到的影响更大。事实上，与对照组患者相比，AD F2 区的 CREB ​​结合蛋白（CBP）、P300/CBP 相关蛋白（PCAF）、组蛋白脱乙酰酶 1（HDAC1）和 HDAC2（但不是 HDAC3）水平显着降低，而海马区只有HDAC1下降，CBP呈下降趋势。在组蛋白水平上，我们检测到额叶皮层中总（H3 和 H2B）组蛋白水平显着增加，但这些在核提取物中下降，表明该大脑区域的组蛋白运输/分解代谢失调。主要在额叶皮层的细胞核中组蛋白 H3 乙酰化水平增加。这些发现为 AD 大脑中相关酶和组蛋白水平的乙酰化功能障碍提供了证据，这可能是转录失调和 AD 相关认知障碍的基础。他们进一步指出，在疾病末期，额叶皮层 F2 区域的失调比海马体的失调更严重，