Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD.

中文翻译：

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亚型特异性磷酸二酯酶 4D (PDE4D) 表达增加与阿尔茨海默病的病理和认知障碍有关

药理学磷酸二酯酶 4D (PDE4D) 抑制显示出恢复阿尔茨海默病 (AD) 记忆功能的治疗潜力，但可能会引起不良副作用。由于 PDE4D 编码多种异构体，靶向特定异构体可能会提高治疗效果和安全性。在这里，我们调查了 AD 中 PDE4D 同种型表达和 PDE4D DNA 甲基化是否受到影响，以及表达变化是否与病理和认知障碍的严重程度相关。在来自 AD 患者（n = 42）和年龄匹配对照（n = 40）的死后颞叶脑材料中，我们分别使用定量聚合酶链反应和 Illumina 450k Beadarrays 测量了 PDE4D 同种型表达和 PDE4D DNA（羟基）甲基化. 线性回归显示 PDE4D1、-D3、-D5、AD 中的 -D8 表达与相关启动子区域中同时发生的（羟基）甲基化变化。此外，增加的 PDE4D1 和 -D3 表达与更高的斑块和 tau 病理水平、更高的 Braak 阶段和进展的认知障碍相关。未来的研究应该表明特定 PDE4D 亚型的功能作用及其选择性抑制恢复 AD 记忆功能的有效性和安全性。